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In Vitro–In Vivo Correlation (IVIVC): A Strategic Tool in Drug Product
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Research & Reviews: A Journal of Drug Formulation, Development and Production
ISSN: 2394-1944(online)
Volume 3, Issue 3
www.stmjournals.com
In Vitro–In Vivo Correlation (IVIVC): A Strategic Tool in
Drug Product Development
Vivek P. Chavda1,*, Dhaval Shah2, Hemal Tandel2, Moinuddin Soniwala1
1
Department of Pharmaceutics, B. K. Mody Government Pharmacy College, Rajkot, Gujarat, India
2
Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
Abstract
In a recent era many concepts are dealing as an emerging tool for the drug delivery
application like Biopharmaceutical Classification System (BCS), In vitro and In vivo study,
and Bioavailability/Bioequivalence (BA/BE) study etc. To determine Therapeutic efficiency in
vitro is not enough so the concept of In vitro-In vivo correlation (IVIVC) is playing as an
convincing correlation with this for concept of pharmaceutical dosage forms have been a
main focus of attention of pharmaceutical industry, academia, and regulatory sectors.
Formulation, Development and optimization of dosage form is an integral part of research
governed by technology transfer to scale up the manufacturing and then concurrent validation
governed from the marketing of any therapeutic agent which is indeed a time consuming and
costly process. A good correlation is a tool for predicting in vivo results based on in vitro data
using IVIVC which gives indirect cost effective approach to dosage form optimization of trials
in human, fixes dissolution acceptance criteria, and can be used as a tool to substitute for
further bioequivalence studies. IVIVC can be used in the development of new pharmaceuticals
to reduce the number of human studies during the formulation development as the main
objective of an IVIVC is to serve as a surrogate for in vivo bioavailability and to support
biowaivers. This review article represents the FDA guidance, development, evaluation, and
validation of an IVIVC to grant biowaivers, and to set dissolution specifications for oral
dosage forms, biopharmaceutical classification systems (BCS), BCS biowaivers, and
applications of BCS in IVIVC development and concept of mapping. The importance of
dissolution media and methodology and pharmacokinetic studies in the context of IVIVC has
been highlighted. The principles of IVIVC also merged with nonoral products such as
parenteral depot formulations and novel drug delivery systems as well.
Keywords: Fundamentals of IVIVC, Biopharmaceutical Classification System (BCS),
Objectives, Biowaiver, Levels, Correlation, Dissolution methodologies, IVIVC of Novel
Dosage Forms, Applications of IVIVC
*Author of Correspondence E-mail: vivek7chavda@gmail.com
INTRODUCTION
From biopharmaceutical point of view, in
vitro-in vivo correlation (IV-IVC) is a
predictive mathematical treatment describing
the relationship between an in vitro property of
a dosage form (usually the rate or extent of
drug release) and a relevant in vivo response,
(e.g., plasma or urine drug concentrations or
amount of drug absorbed). It is recommended
by various regulatory bodies and mostly
applicable to drug dosage forms for oral routes
and sustained release products. It is a useful
tool for drug dosage form development,
because a successful correlation can assist in
the selection of drug formulation with
appropriate and acceptable dissolution criteria,
and depending on its predictiveness, it can be
used as a forecast or surrogate for further
bioequivalence studies. There are different
categories of IVIVC; A, B, C and D. In the
rapidly emerging field of novel drug delivery
systems, the need to establish correlation
between in vitro drug release (dissolution) data
and in vivo drug profiles is ever growing. Such
correlations would not only allow more
efficient drug and product development but
also economize resources and lead to
improved product quality. The bioavailability
implications of dissolution should never be
accepted on faith; rather it has to be proved
through carefully designed in vitro-in vivo
correlation studies. Long back, Wagner had
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(IVIVC): A Strategic Tool in Drug Product Development
stated that, “Future research in dissolution
rate should be directed mainly towards
establishing correlation of in vitro data with in
vivo data.”
PURPOSE OF IVIVC [1]
Reduction of Regulatory Burden
IVIVC can be used as substitute for additional
in vivo experiments, under certain conditions.
Optimization of Formulation
From the number of trials the main focus is
given to the optimization of formulations may
require slight modification in the composition,
procedural steps of manufacturing process,
equipment, apparatus and batch sizes. The
main focus is given in the development of
newer dosage form is to prove novelty of a
new formulation, which is bioequivalent or
surpass the equivalency with a target
formulation, a considerable amount of efforts
with the skilled usage of software now-a-days
helps to reduce the number of trial.
JUSTIFICATION FOR
THERAPEUTIC’
PRODUCT QUALITY
IVIVC is often adequate for justification of
therapeutically
meaningful
release
specifications of the formulation.
Scale up post approval changes (Time
and cost saving during the product
development)
This SUPAC guideline provide the guidance to
sponsors of new drug applications (NDA's),
abbreviated new drug applications (ANDA's),
and abbreviated antibiotic applications
(AADA's) who intend, in the period of the post
approval, to any change comes under:
1. The components or composition;
2. The site of manufacture;
3. The scale-up/scale-down of manufacture;
and/or
4. The
manufacturing
(process
and
equipment) of an immediate release oral
formulation.
For the filings of a Level 3 (or Type II in
Europe) variation, properly governed IVIVC is
also serves as justification for a biowaivers
either during scale up or post approval, as well
as for line extensions, (e.g., different dosage
strengths). The guidance is helpful in
Chavda et al.
determination
of
level
of
changes,
recommended suggestion at every production
steps, changes related to IVIVC at every
predetermined step, documented procedure for
the changes with the application of 21 CFR
compliance report.
IVIVC as Surrogate for in vivo
Bioequivalence and to Support
Biowaivers (time and cost saving)
The purpose behind the utilization of IVIVC
model is to justify the in vitro dissolution
profiles as a surrogate for in vivo
bioequivalence and to support the biowaivers.
DEFINITIONS AND LEVELS
OF CORRELATION
In a true mathematical sense a correlation is a
measure of the relation between two or more
quantitative variables with a correlation
coefficient justify the closeness of the
relationship. While relationships between in
vitro and in vivo parameters, irrespective of the
mathematical definition of the term gives
essence of biopharmaceutical stand-point [2].
Various definitions of IVIVC have been
proposed by the International Pharmaceutical
Federation (FIP), The United States
Pharmacopeia (USP) working group, and by
regulatory authorities such as the Food and
Drug Administration (FDA) or European
Medicines Agency (EMEA) [3–6].
USP defines IVIVC as the establishment of
relationship between a biological property, or
a parameter derived from a biological property
produced by a dosage form, and a
physicochemical property or characteristic of
the same dosage form [4].
FDA defines IVIVC as a predictive
mathematical
model
which
describes
relationship between in vitro properties of a
dosage form and a relevant in vivo response
[3].
Generally, the in vitro dissolution rate and in
vivo input rate of active material is considered.
From these definitions, various levels of
correlation have been defined.
Level A
Level A correlation is usually estimated by a
two stage procedure: deconvolution followed
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
by comparison of the fraction of drug absorbed
(in vivo) to the fraction of drug dissolved (in
vitro). It is a linear correlation which justifies a
point-to-point relationship between in vitro
dissolution and the in vivo input rate of drug.
In a linear correlation, the in vitro dissolution
and in vivo input curves may be directly super
imposable or may be made to be super
imposable by the use of a scaling factor [2].
Nonlinear correlations, while uncommon, may
also be appropriate. Alternative approaches to
developing a Level-A IVIVC are possible [7].
One alternative is based on a convolution
procedure that models the relationship
between in vitro dissolution and plasma
concentration in a single step. Plasma
concentrations predicted from the model and
those observed are compared directly. For
these methods, a reference treatment is
desirable, but the lack of one does not preclude
the ability to develop an IVIVC. Whatever the
method used to establish a Level-A IVIVC, the
model should predict the entire in vivo time
course from the in vitro data. The percent of
drug absorbed may be calculated by means of
model-dependent techniques such as the
Wagner-Nelson procedure (only for one
compartment kinetics, extravascular route) or
the Loo-Riegelman method (for two
compartments, extravascular and intravenous
route) or by model-independent numerical
deconvolution (for all compartment by
extravascular and intravenous route) or
method of residual for two or more
compartment while incremental method for
two compartment extravascular route. When in
vitro curve and in vivo curve are super
imposable, it is said to be 1:1 relationship,
while if scaling factor is required to make the
curve super imposable, then the relationship is
called point-to-point relationship [8]. Level-A
correlation is the highest level of correlation
and most preferred to achieve; since it allows
bio waiver for changes in manufacturing site,
raw material suppliers, and minor changes in
formulation [4].
Level B Correlation
Level B IVIVC is based on statistical moment
analysis. The mean in vitro dissolution time
(MDT) is compared with statistical moments
either to the mean residence time or to the
mean absorption time [7]. Despite of
involvement of all of the in vitro and in vivo
data level B correlation is not considered to be
a point-to-point correlation as a number of
different in vivo curves will produce similar
mean residence time values. Hence least useful
for regulatory purpose and to justify extremes
of quality control standards [9].
Level C Correlation
Level C IVIVC is a single-point relationship
between a dissolution rate (in vitro) and AUC,
Cmax, Tmax, Ka or time to have 10, 25, 50 and
90% absorbed (in vivo) [2]. A Level C
correlation does not give clear idea about the
plasma concentration time profile, which is the
critical factor that defines the performance of
any controlled release product hence not so
much reliable but has a good impact in the
early stage of formulation development [3].
Multiple Level C Correlations
A multiple Level C correlation relates one or
several in vivo pharmacokinetic (P.K.)
parameters of interest as described in Level C
to the amount of drug dissolution
rate/efficiency [9]. It can be used to endorse
biowaiver if dissolution is commenced with at
least three time point. Level A correlation is
likely to develop, when multiple correlation is
established at each time point for the same
P.K. parameter [3]. Level B and C correlations
can be useful in early formulation
development,
including
selecting
the
appropriate
excipients,
to
optimize
manufacturing processes, for quality control
purposes, and to characterize the release
patterns of newly formulated immediaterelease and modified-release products relative
to the reference [2].
Level D Correlation
It is a semi quantitative and/or qualitative
analysis which is eccentric and rank order
correlation and is not considered useful for
regulatory purpose, but allows the distinction
between two main types of correlations in
simple terms act as copula for formulation
development and any post approval changes
[7, 8]. Level A directly uses dissolution data
while Level B and C need more data for the
establishment of IVIVC. The FDA ranked the
levels as follows: A Level A IVIVC is
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(IVIVC): A Strategic Tool in Drug Product Development
considered to be the most informative
followed by multiple Level C correlations.
However, if a multiple Level C correlation is
not possible, then a Level c or B correlation is
recommended [10].
In vivo Data
The plasma concentration curve is one of the
most common representation of drug in the
body obtained after administration of
formulation to healthy volunteer (Figure 1); it
depends on drug input within the blood flow,
which depends on the dosage form and the
properties of the drug such as solubility,
dissolution rate, particle size, crystal shape,
polymorphism, pKa, and stability in
gastrointestinal tract (GIT), and thereafter its
pharmacokinetics input processes (First Pass
Effect (FPE), location and type of absorption).
The disposition of the drug afterwards depends
only on the drug and patient [11, 12].
The model-independent parameters (derived
from the curve) such as Area Under Curve
(AUC), Maximum Concentration Achieved
(Cmax), Time required to achieve Cmax
(Tmax) to estimate, respectively, the amount
Chavda et al.
and rate (bioequivalence parameters), MRT
and other parameters such as half value
duration (HVD: duration over Cmax/2) or
Cmax/AUC. Here Figure 1 shows how a
formulation travels and what happens after its
oral administration. In vivo dissolution and in
vivo absorption are linked; the release of the
active ingredient and its dissolution allows its
absorption as in most cases only the
nonionized dissolved active ingredient can
cross the membranes.
The accurate justification of absorption that
reflect the release from the dosage form and
the drug absorption can be calculated by
various methods as stated by the FDA. The
usual techniques given in Table 1 helps to
estimate the in vivo absorption or dissolution
time
course
using
an
appropriate
deconvolution-technique for each formulation
and subject, (e.g., Wagner-Nelson, numerical
deconvolution). After the completion of all the
calculations the graphical representation made
to study the absorption pattern by plotting the
curve of the percent of the fraction of dose (%
FD) absorbed versus time.
Fig. 1: Various Phenomena Observed after Administration of Tablets.
Table 1: Various Methods used to Determine the Input (absorption) Kinetic [11].
Model
First order input
Other order input
Residual (EV)
Wagner Nelson (EV)
1 compartment
Wagner Nelson (EV)
Deconvolution (EV + IV)
Deconvolution [EV + intravenous (IV)]
Residual
Loo-Riegelman (EV + IV)
Loo-Riegelman (EV + IV)
2 compartment
Incremental (EV)
Incremental (EV)
Deconvolution (EV + IV)
Deconvolution (EV + IV)
Residual (EV)
More than 2 compartment
Deconvolution (EV + IV)
Deconvolution (EV + IV)
EV, only the extra vascular (EV) administration is needed; IV þ EV, EV and IV administration or at least per os solution and
EV administration are needed simultaneously.
More than one dosage units are used for the
estimation of proper IVIVC and if possible
comparison made with or solution is essential
to calculate deconvolution. Pharmacokinetics
and absorption of the drug should be linear.
The comparison between formulation and its
RRJoDFDP (2016) 31-54 © STM Journals 2016. All Rights Reserved
Page 34
Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
simulated data cannot be predicted in case
where the pharmacokinetic processes are
dependent on the fraction of dose reaching the
systemic blood flow (or of the dose
administered) or on the rate of absorption. The
observations made on nonlinearity may be
owing to saturation of molecule at absorption
site (active absorption), induction or inhibition
of the metabolism, the first past effect, which
is rate/absorption dependent, etc. are the
probability. Those probability needs to be
cross connected before attempting the IVIVC
which helps to nullify the limiting factor, if the
solubility is not the limiting factor in
comparison to the drug release, an IVIVC may
be attempted. It is helpful if the release
governed through the formulation compared to
molecular property, and must be the slowest
phenomenon
versus
dissolution
and
absorption.
In vitro Data [13–17]
In order to compare the in vivo absorption
profile with in vitro data, an in vitro profile
must be obtained by dissolution tests which
differ in many ways compared to in vivo. Any
method which can discriminate between the
formulations can be used but certain
techniques tend to be preferred, i.e., paddle,
flow through cell, and basket (USP II, IV, I,
respectively). In addition, aqueous media is
preferred (pH not exceeding 6.8 or 7.2); for the
poorly soluble drugs use of surfactant is
acceptable. Composition of media varied from
type and purpose of study, i.e., media to mimic
fasted and fed state such as the fasted state
simulated intestinal fluid and fed state
simulated intestinal fluid media. For the
comparison of release profile and release
pattern in vitro different dosage forms must be
analyse with the same media and apparatus.
The compendial apparatus for dissolution as
per USP are:
1. Apparatus 1 (rotating basket),
2. Apparatus 2 (paddle assembly),
3. Apparatus 3 (reciprocating cylinder),
4. Apparatus 4 (flow-through cell),
5. Apparatus 5 (paddle over disk),
6. Apparatus 6 (cylinder),
7. Apparatus 7 (reciprocating holder).
Graphical representation for the percentage
dissolved versus time enables the calculation
of some derived parameters like time to have
10, 50, or 90% of the drug dissolved, called
T10, T50, and T90%, respectively or mean
dissolution time (MDT). Those models are
linked to dialysis membranes, which allow the
absorbable fraction of dose to be estimated.
These systems belong to the class of Artificial
Digestive Systems (ADS). As opposed to the
classical dissolution systems, they can meet
the following physiological requirements: (i)
sequential use of enzymes in physiological
amounts; (ii) appropriate pH for the enzymes;
(iii) removal of the products of digestion; (iv)
Mixing at each stage of digestion; (v)
physiological transit times for each step of
digestion; and (vi) a peristaltic dynamic
approach. The most important parameters
which are considered for simulating in vivo
conditions are pH, buffer composition, buffer
capacity, temperature, volume, hydrodynamics
etc. Noncompendial media are widely used
with apparatus suitability test and have shown
better IVIVC as compared to Compendial
media. USP Type I and II apparatus calibrated
with the use of disintegrating as well as
nondisintegrating calibrator tablets and it is the
only standardized approach to establish
apparatus suitability for conducting dissolution
tests.
IVIVC and the BCS
When a drug is administered orally, various
phenomena occur in addition to the
biopharmaceutical process of drug release
from the dosage form. The solubilization of
the active ingredient will depend on its
physicochemical
characteristics
(polymorphism, size of particle, pKa, Log P,
etc.) as well as its absorbability (pKa-pH, Log
P); its absorption will depend on its
permeability, the mechanism (passive, active,
etc.) of absorption, and also on the presence or
not of efflux [18,19]. Solubility and
permeability are the two main parameters for
classified drugs in the biopharmaceutics
classification system (BCS), taking into
account the therapeutic dose. The BCS
introduced in the mid-1990s is defined in the
FDA guidelines as follows:
“The BCS is a scientific framework for
classifying drug substances based on their
aqueous
solubility
and
intestinal
permeability.”
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(IVIVC): A Strategic Tool in Drug Product Development
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 immediate release (IR)
solid oral dosage forms: dissolution, solubility,
and intestinal permeability [19]. The
classification is associated with drug
dissolution and absorption model, which
identifies the key parameters controlling drug
absorption as a set of dimensionless numbers:
the Absorption number, the Dissolution
number and the Dose number.
 The Absorption number is the ratio of
the mean residence time to the absorption
 time.
 The Dissolution number is a ratio of
mean residence time to mean dissolution
 time.
 The Dose number is the mass divided by
an uptake volume of 250 ml and the drug’s
 solubility.
 The mean residence time here is the
average of the residence time in the
 stomach, small intestine and the colon.
 The fraction of dose absorbed then can
be predicted based on these three
parameters. For example, Absorption
number 10 means that the permeation
across the intestinal membrane is 10 times
faster than the transit through the small
intestine indicating 100% drug absorbed.
According to the BCS, drug substances are
classified as follows with the need of
Chavda et al.
correlation with IVIVC approach which is
discussed in Table 1.
Classification is governed through the
influence of formulation and relevant
excipients. The controlled release profile is
possible by selecting the proper dosage forms
which can change the solubility classification
into a “release characteristic” which also helps
in the proper establishment of IVIVC. The
absorption kinetics barely affected if the
absorption is a limiting factor of drug to its
release (mainly BCS Class III drugs) and
consequent in vivo behavior of the drug.
Release rate will be lowered for the drugs
having dissolution as a limiting factor so here
drug alone can forms a modified or slow
release form (Table 2 & 3). For BCS Class 2
where permeability is faster than the
dissolution rate and BCS Class 4 where
solubility is also limited with the permeability,
increasing of the dissolution and permeability
both can be achieved by physical or chemical
or galenical processes. The gastrointestinal
(GI) tract acts as a natural sinker where
continuous blood supply increases the
absorption rate. The drug could be absorbed as
soon as it dissolves in Class 2 especially. For
the drug which have a relatively good
bioavailability (F) and no solubility or
absorption problems in regards to the release
from the formulation that must be the limiting
factor, the IVIVC could only be ascertained
(Table 3).
Table 2: Bio Pharmaceutics Drug Classification and Expected IVIVC for Immediate Release Drug
Products.
Class
Ι
Solubility
High
Permeability
High
ΙΙ
Low
High
ΙΙΙ
High
Low
IVIVC
Correlation (if dissolution is rate limiting step)
IVIVC expected (Correlation is possible if the release is slower than the
dissolution itself)
Little or no IVIVC (no correlation is possible as the absorption is the limiting step)
ΙV
Low
Low
Little or no IVIVC (correlation is possible in limited cases)
Table 3: Bio Pharmaceutics Drug Classification for Extended Release Drug Products [11].
Class
ΙA
Solubility
High and Site Independent
ΙB
High and Site Independent
ΙΙA
Low and Site Independent
ΙΙB
Low and Site Independent
Va: Acidic
Variable
Permeability
High and Site Independent
Dependent on site and Narrow
Absorption Window
High and Site Independent
Dependent on site and Narrow
Absorption Window
Variable
Vb: basic
Variable
Variable
RRJoDFDP (2016) 31-54 © STM Journals 2016. All Rights Reserved
IVIVC
IVIVC Level A expected
IVIVC Level A expected
IVIVC Level C expected
IVIVC Level A expected
Little or no IVIVC
Little or no IVIVC
Page 36
Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
Fig. 2: The Product Development Process for Extended-release Products. [11]
SYSTEMATIC DEVELOPMENT OF A
CORRELATION
Scientifically sound approach of IVIVC or
IVIVR ("R" denoting "relationship") can
easily be understood from Figure 2.
An assumed IVIVR is essentially one that
provides the initial guidance and direction for
the early formulation development activity.
Stage 1 is retrospective IVIVR which is
devised from extensive in vitro data and from
in vivo study. With a defined formulation that
meets the in vivo specification, Stage 2
commences. With good understanding and
appreciation of defined formulation and its
characteristics, a prospective IVIVR is
established through a well-defined prospective
IVIVR study. Once the IVIVR is established
and defined it can be then used to guide the
final cycle of formulation and process
optimization leading into Stage 3 activities of
scale-up, pivotal batch manufacture, and
process validation culminating in registration,
approval and subsequent post-approval scale-
up and other changes. Thus rather than
viewing the IVIVR as a single exercise at a
given point in a development program, one
should view it as a parallel development in
itself starting at the initial assumed level and
being built on and modified through
experience and leading ultimately to a
prospective IVIVR. The use of the term
IVIVR rather than IVIVC is preferred.
Immediate release products are amenable to
dissolution-absorption analysis.
However, the term IVIVR itself is neither new,
nor fundamental. Rather, what is needed is a
better understanding of in vivo dissolution, and
it’s in vitro surrogate, the dissolution test.
Additionally, dissolution needs to be
considered in the context of other parallel and
sequential processes, (e.g., permeability,
degradation, and transit). Through a better
understanding of dissolution, dissolution and
IVIVR can facilitate not only SUPAC-type
changes, but also facilitate drug product
development.
RRJoDFDP (2016) 31-54 © STM Journals 2016. All Rights Reserved
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(IVIVC): A Strategic Tool in Drug Product Development
IVIVC Methodology
Level A is the one offering biggest scope. This
correlation that uses all the available data is
the only one to allow a full in vivo profile to be
simulated from a set of in vitro data. For this
reason, this level and only this one is
recognized to allow in vitro data to be a
surrogate of in vivo for post approval change.
Numerous requirements exist for establishing
correlations and many of them have been
described in the previous sections [20].
To evaluate the dual nature of drug and dosage
form, pharmacokinetic and pharmacodynamic
both the activities were evaluated and
compared with the best interest of the linearity
[21]. In addition the moiety is the only
responsible for the therapeutic activity which
must be known. All analytical methods must
be established and validated for the adequate
valuation of drug or its active metabolite in the
plasma (sometimes serum is also choice of
sample to evaluate the drug in vivo. Inter as
well as intra individual variability must be
quantifiable. If the variability is extensive,
modifications in the drug dosage form may be
hidden by the variability, or vice versa,
modification observed in vivo may only be
owing to variability and not the formulation.
The linear pharmacokinetic profile of the drug
is required to establish the correlation. If the
first pass effect depends on the initial
concentration of the drug, the drug may have
linear pharmacokinetics but nonlinear input
kinetics which is also the possibility to be
evaluated. The drug absorption must be a
passive, windowless, nonsaturable process for
the linear kinetic [22].
The controlled and delayed release dosage
forms are designed in such a way that their
absorption must be limited from the drug
dosage form. For the identical convolutions
and deconvolution, drug needs to be
administered by intravenous injection or a
solution. In some rare cases, only the
formulation which of the interest may be
needed; if the apparent model is a onecompartment model. Numerous dissolution
methods (not limited to those officially
prescribed) must be available to ensure proper
discrimination as well as the use of various
media are the necessary things for the in vitro
Chavda et al.
profile prediction and evaluation. The
preferred dissolution apparatus is USP I
(basket), II (paddle), or IV (flow through cell);
from which type IV is mainly used for the
drugs which have low solubility and helps to
predict their in vitro behaviors.
An aqueous medium, either water or a
buffered solution, with adjusted pH preferably
not exceeding pH 6.8 (or 7.2), is
recommended, other pH must be justified
according to absorption profile of the
molecule. Surfactant addition is acceptable for
the poorly soluble drugs which can mimic the
in vivo behavior while bile juice secreted from
the liver to intestine. Dissolution apparatus
designed in such a way that twelve individual
dosage units from each batch can be used for
dissolution with the same outer temperature
maintained and at the every time point the
same quantity of the media will be instilled
from the same thermostatic buffer.
The sampling points should reflect the
dissolution profile. The concentration for
every time point evaluated with the corrected
concentration. The coefficient of variation
(CV) less than 10% of the mean dissolution
profiles of a single batch should be accepted.
Establishment of a Level A correlation is
appropriate only after single administration, as
it is a pharmaceutical parameter.
In some rare cases steady-state correlations
may be indicated but it is suggestive to include
the assumption that the phenomena and
relationships
observed
after
single
administration persist in a steady state in the
same extent and form. IVIVCs are usually
developed in the fasted state. Absorption of
drug studied for both fasted and fed condition
to study whether a drug can tolerate which
state. In addition, correlations are also limited
by numerous factors: correlation cannot be
extrapolated in following cases;
1. From a single type of dosage form it
cannot be extrapolated to another type of
dosage form.
2. To route of administration cannot be
extrapolated to another one.
3. If release is not the limiting factor.
The IVIVCs must be established as early as
possible in the development of a modified
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
release pharmaceutical dosage form which
helps to understand the biopharmaceutical fate
and accelerating the development of proper
dosage form. For a given drug, a correlation is
related to the dosage form or type of dosage
form. Modification of the excipients and
formulation should not radically modify the
product design and release mechanism in order
to use the same IVIVC equation. The IVIVC
equation is a simple relationship of in vitro
results (expressed as X as assumed to be less
variable) with in vivo results (expressed as Y).
The use of nonlinear model are allowed but
must be justified. The IVIVC can be
established using;
1. Pharmacological correlations based on
clinical observations.
2. Semi quantitative correlations based on the
drug blood levels or urinary excretion
data.
3. Quantitative correlations arising from
absorption kinetics and calculation of in
vivo dissolution rate and absorption rate
constants.
It may be quantitative correlation using linear
equation or simple rank order correlation.
There are three types of methods which are
widely used which are described as follows:
Simple Point Type
The percentage of drug dissolved in a given
time or the time taken for a certain percentage
of drug to be dissolved, is correlated with
certain parameter of the bioavailability.
Comparison of Profiles
The entire in vivo response time profile can be
correlated to the entire dissolution rate time
curve. Some of the in vivo and in vitro
parameters employed for correlation are given
in Table 4.
Direct, Differential-Equation-Based
Single and multiple kind of compartment
pharmacokinetic models and a corresponding
system of differential equations are used in
vitro-in vivo correlation (IVIVC) method is
proposed that directly relates the time-profiles
of in vitro dissolution rates and in vivo plasma
concentrations. The rate of in vivo input is
connected to the rate of in vitro dissolution
through a general functional dependency that
allows for time scaling and time shifting. A
multiplying factor which is known as the
variability of absorption conditions as the drug
moves along is also incorporated. Two
parameter and 4-parameter fit curve helps to
simplify the complex understanding of the
evaluation system. Two data sets incorporating
slow-, medium-, and fast-release formulations
are used to test the applicability of the method.
All fitted parameters had realistic values, and
good or acceptable fits and predictions are
evaluated by using plasma concentration
which gives idea about the mean squared
errors and percent AUC errors. Introduction of
step-down functions that account for the transit
of the dosage form past the intestinal sites of
absorption proved useful. The presented
methods can provide increased transparency,
improved performance, and greater modeling
flexibility [23].
Table 4: IVIVC Parameters.
In vivo data
Plasma conc. time profile
Plasma concentration at time t,

C max,


tmax,
t
∞
AUCo AUCo

t30% t50% t90%

Pharmacokinetic parameters
Absorption and elimination rate

constant and half life
Percent drug absorbed time profile
Statistical moment analysis
MRT, MAT

In vitro data
Percent drug dissolution profile
Percent drug dissolved at time t,

tmax,


Time taken for maximum amount of drug to dissolve.
Total amt. of drug dissolved.

Time for a certain percentage of drug to dissolve such as

t30% t50% t90%
Kinetic parameter
Dissolution rate constant.

Dissolution half life

Percent drug dissolved time profile
Percent drug dissolved at time t

Statistical moment analysis
MDT

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(IVIVC): A Strategic Tool in Drug Product Development
Power Law IVIVC
Most correlations between in vitro and in vivo
data (IVIVC) rely on linear relationships.
However, nonlinear IVIVC can be also
observed, justified and validated. The purpose
of the present work was the development of a
methodology for power law IVIVC, which
mirror power law kinetics under in vitro and in
vivo conditions. Fractional calculus was used
to justify power law kinetics for zero-order
processes in disordered media. Power law
kinetics was observed in a large number of in
vitro data sets. When “zero order” release and
absorption is considered in terms of fractional
calculus the following power law IVIVC
between the fraction released Fr and the
fraction absorbed Fa, is obtained: Fa = µFrƛ –
β, where, µ is a constant related to the rate
constants
and
the
orders
of
the
release/absorption kinetics, ƛ is the ratio of the
orders of the kinetics under in vitro and in vivo
conditions and ¡ accounts for a time shift
between the in vitro and in vivo processes [24].
Important Considerations in Developing
a Correlation [25, 26]
1. When factors like pH, osmotic pressure,
enzyme, ionic strength, presence of
digestive material, presence of food, and
pathological conditions, etc. are not the
factors which will affect the dissolution
profile of the dosage unit than a set of
dissolution data obtained from one
formulation is correlated with a
Chavda et al.
2.
3.
4.
5.
6.
7.
8.
deconvoluted plasma concentration-time
data set.
In a linear correlation, the in vitro
dissolution and in vivo input curves may
be directly super imposable or it may be
super imposed using appropriate scaling
factor (time corrections).
The correlation is still considered as a
valid correlation if one or more of the
formulations may not have the similar
relationship with that of in vitro
performance and in vivo profiles compared
with the other formulations.
The in vitro dissolution methodology
should be able to adequately discriminate
between the study formulations.
During the early stages of correlation
development, dissolution conditions may
be altered to different trial to attempt to
develop a one-to-one also known as direct
correlation between the in vitro dissolution
profile and the in vivo dissolution profile.
An established correlation is valid only for
a specific type of pharmaceutical dosage
form (tablets, gelatin capsules, etc.) with a
particular release mechanism (matrix,
osmotic system, etc.) and particular main
excipients.
IVIVC extrapolation is established in the
healthy subjects to patients has to be taken
into account.
The percent dissolved is measured for the
release rate estimation, for each
formulation studied, should differ
adequately, (e.g., by 10%).
Fig. 3: IVIVC Methods.
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
Example: Level A Correlations Methodology
The purpose of Level A correlations is to
define a direct relationship between in vitro
and in vivo data so that measurement of the in
vitro dissolution rate alone is sufficient to
determine the biopharmaceutical fate of the
dosage form. IVIVCs should be sought as
early as possible during the dosage form
development (a prior correlation). In some
cases, formulation has been undertaken rapidly
and correlations sought on the finished product
from subsequent in vitro tests (Figure 3). The
predictive power of these correlations (a
posteriori correlation) is thus limited, and they
require additional validation.
Predictability of Level A Correlation
The major aim of IVIVC as presented in the
previous steps is the power of predictability of
the simulations based on this relationship
(Figure 4). IVIVC must predict the in vivo
bioavailability results from in vitro dissolution
data and this simulation must reflect the in
vivo behavior of the various formulations
(Figure 5). The error associated with this
prediction must be known and is evaluated
using the predictability.
Two types of predictability are referenced:
internal predictability based on the initial data
and external predictability based on a new set
of data (new formulations), this latter
predictability being really a validation process.
For external predictability, new formulations
are needed, i.e., to establish IVIVC and then to
initiate and validate it at minimum three to
four formulations are needed. Predictability is
not needed if in vitro release is independent of
the conditions (apparatus and pH), and in this
case one formulation may be enough, (e.g., a
certain type of osmotic release oral system
(OROS) tablets) [25, 26].
Level B/C Correlation Methodology
Level B or C correlations help to establish the
direct relationship of in vitro parameters
versus in vivo parameters between in vitro and
in vivo parameters. As it is a point-to-point
relationship, each point reflects one
formulation. The possible parameters can be
Mean Residence time (MRT) versus Mean
Dissolution time (MDT) for Level B and
Cmax (Maximum Concentration achieved)
versus T50 (time require for the 50% of drug to
be absorbed) for Level C. Level C IVIVC is
defined in the FDA note for guidance as: “A
single point Level C correlation allows a
dissolution specification to be set at the
specified time point. While the information
may be useful in formulation development,
waiver of an in vivo bioequivalence study
(biowaiver which helps to reduce the testing
for the commercial batch) is generally not
possible if only a single-point correlation is
available”.
Fig. 4: Scheme for IVIVC.
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(IVIVC): A Strategic Tool in Drug Product Development
Chavda et al.
Fig. 5: Prediction based in IVIVC.
Level B correlations are based on statistical
moment techniques and not on more classical
Pharmacokinetic (PK) or in vitro parameters.
PK classical parameters can reflect all the
bioequivalence parameters and give a good
description of the curves whereas a number of
different in vivo curves like AUC versus time
help to produce similar mean residence time
values, Cmax, and Tmax, T50 etc which we is
called multiple-point Level C correlation.
This correlation “may be used to justify a
biowaiver, helps to establish over the entire
dissolution profile with one or more
pharmacokinetic parameters of interest”. But if
all the parameters describing the input rate and
amount of drug in the body are used to
establish a multiple Level C correlation, then a
Level A correlation may exist and must be
sought [11].
Predictability of Correlation
It can be calculated by prediction error that is
the error in prediction of in vivo property from
in vitro property of drug product. Based on
therapeutic index of the drug and application
of IVIVC, evaluation of prediction error
internally or externally may be appropriate.
Internal error provides a basis for acceptability
of model while external validation is superior
and affords greater confidence in model [15,
21, 27].
In short it is a model validation part. The %
prediction error can be calculated by the
following equation:
% Prediction error (P.E) = (Cmax observed –
Cmax predicted) × 100/Cmax observed
Internal Predictability
Using IVIVC one can predict the
bioavailability and related parameters like
Cmax, Tmax, and AUC for the formulation
using
in
vitro
property.
Predicted
bioavailability compared with observed
bioavailability for Percent prediction error (%
P.E) establishment. According to FDA
guidelines, the average absolute %P.E should
be below 10% and %P.E for individual
formulation should be below 15% for
establishment of IVIVC.
External Predictability
The predicted bioavailability is compared with
known bioavailability and % error is
calculated. Here two possibilities are evaluated
1. The prediction error for external validation
should be below 10%.
2. % P.E. between 10 and 20% indicates
inconclusive predictability and need of
further study using additional data set.
Drugs with narrow therapeutic index, external
validation is required.
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
EVALUATION OF IVIVC
From the application of an IVIVC and the
therapeutic index of the drug molecule,
evaluation of prediction error (% PE)
internally and/or externally may be
appropriate. Internal predictability is based on
the initial data used to define the IVIVC model
using formulations with three or more release
rates for nonnarrow therapeutic index drugs
exhibiting conclusive prediction error while
external predictability is based on additional
test data sets. If two formulations with
different release rates are used to develop
IVIVC, then the application of IVIVC would
be limited to specified categories. Under many
of the circumstances, for complete evaluation
and subsequent full evaluation of application
of the IVIVC, prediction of error externally is
easy and better tool [11].
External
predictability
evaluation
is
fundamental tool only in case where
 The drug possesses a narrow therapeutic
index.
 Only two release rates were used to
develop the IVIVC.
 The internal predictability criteria are not
met, i.e., prediction error internally is
inconclusive.
However, since the IVIVC will potentially be
used to predict the in vivo performance for
future changes from the in vitro, it is of
calculus part to evaluate external predictability
when additional data are available. The
objective of IVIVC evaluation is to estimate
the magnitude of the error in predicting the in
vivo bioavailability results from in vitro
dissolution data. This objective should guide
the choice and interpretation of evaluation
methods. Any appropriate approach related to
this objective may be used for evaluation of
predictability of the IVIVC [20].
BIOWAIVER FOR BCS CLASS I
Drug having good stability in GIT and narrow
therapeutic index with less excipient
interaction can affect at negligible course to
the absorption of drug in the oral cavity. On
the basis of FDA guidelines, sponsor can
request biowaiver for BCS Class I in
immediate release solid oral dosage form
which opts above discussed property. Once a
drug travels through stomach; it gets
solubilized in gastric fluid rapidly before
gastric emptying and the rate and extent of
absorption is independent of drug dissolution
as in case of solution. Hence, the goal of
biowaiver can be fulfilled [28,29].
BIOWAIVER EXTENSION
POTENTIAL FOR BCS CLASS II
For the BCS Class II drugs, the rate and extent
of absorption of depends on in vivo dissolution
behavior products. The in vivo bioequivalence
study can be waived only if in vivo dissolution
can be predicted from in vitro dissolution
studies [29]. In vitro dissolution methods can
mimic in vivo dissolution behavior of BCS
Class II drug and are appealing but
experimental methods can be difficult to
design, statistical software’s knowledge is the
necessary for the proper justification and
validated method of analysis is the key
requirement.
BIOWAIVER EXTENSION FOR
BCS CLASS III
Excipients selected with a view to their
inactive characteristics used in two
pharmaceutically equivalent; one is solid oral
immediate release product does not affect the
drug absorption and the second is products
dissolves very rapidly (>85% in 15 min.) in all
relevant pH ranges, there is no reason to
believe that these products would not be
bioequivalent [11].
Application of Level a Correlation to
Set Dissolution Limits
Level A correlations are a powerful
development tool due to their timely and
guarantied in vivo performances. In addition,
they provide one of the tools used to guarantee
the full process and quality of the final
product. It was already discussed that if
specification is ± 10% range can be accepted
provided the range at any time point which
does not exceed 25%. Widening specifications
based on scale-up, stability, or other lots for
which if bioavailability data are unavailable,
they are not recommended for the
establishment. In the presence of an IVIVC,
the FDA stated that “If an in vitro in vivo
correlation is established, the dissolution
test—after proper validation and verification
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(IVIVC): A Strategic Tool in Drug Product Development
can be used as a qualifying quality control
method with the in vivo relevance, while in
case of the absence of an IVIVC, the
dissolution test can be used only as quality
control method”. In this case, the limits are set
after calculating the plasma concentration
(from in vivo) time profile using convolution
techniques or other appropriate modeling
techniques, and determining whether the
batches with the fastest and slowest release
rates allowed by the dissolution specifications
result in a maximal difference of 20% in the
Cmax and AUC. IVIVC generally allow the
setting of wider dissolution specifications than
the usual 10%. This would be dependent on
the predictions of the IVIVC, (i.e., 20%
differences in the predicted Cmax and AUC)
[11].
Why IVIVC Fail for Immediate
Release Dosage Form
The fraction of drug absorbed (Fa) is plotted
against the fraction drug dissolved (Fd) for the
Level A analysis. The fraction of drug
absorbed can be calculated and profile
obtained by deconvoluting the plasma profile.
Deconvolution is essentially a back calculation
to answer the question: "What must the drug
absorption profile have been, given the plasma
profile?" A statistic curve from Level A
analysis gives the correlation coefficient value
known as R2, it ranges from zero to maximum
of one and is a measure of the strength of
relationship between Fa against Fd. Often,
results with sufficiently large r2, (e.g., greater
than 0.9) yielded "a (successful) correlation"
which gives a direct relationship between two
measurements. An r2 value that was too low
resulted in a "no correlation" between
compared results. Only products with
dissolution rate-limited absorption and gives
the complete absorption of the drug can be
expected to exhibit a Level A plot with a slope
of one and zero intercept, immediate release
products will "fail" the Level A method [27,
30].
PARAMETERS TO BE CONSIDERED
WHILE DEVELOPING IVIVC
Metabolic Factors
A drug must enter in systemic circulation from
liver once it is absorbed from the
gastrointestinal lumen, as blood perfusion to
all gastrointestinal tissues drain into the liver
Chavda et al.
via the hepatic portal vein [31]. Drug loss may
occur in the GIT due to the instability of the
drug in the GIT in acidic environment and/or
due to Complexation of drug with the
components of the GI fluids, food, formulation
excipients or other co-administered drugs [32].
Apart from that the drug may also be
influenced by GI enzymes and components of
liver [33].
Drug Loss in G.I.T
Enzymatic and/or nonenzymatic reaction that
completes with the absorption of a drug may
reduce oral bioavailability of that particular
drug. Acid hydrolysis is a common
nonenzymatic reaction. Enzymes of the
intestinal epithelium and within the intestinal
microflora metabolize some drug. The reaction
products are often inactive or less potent than
the large molecule [32]. Metabolism or
degradation by enzymes or chemical
hydrolysis may adversely affect the drug
absorption.
Gastric Emptying Rate
A swallowed drug rapidly reaches the stomach
which empties its contents into the small
intestine. Because the duodenum has the
greatest capacity for the absorption of drugs
from the GI tract, a delay in the gastric
emptying time for the drug to reach the
duodenum will slow the rate and possibly the
extent of drug absorption, thereby prolonging
the onset time for the drug. Some drugs, such
as penicillin, are unstable in acid and
decompose if stomach emptying is delayed.
Other drugs, such as aspirin, may irritate the
gastric mucosa during prolonged contact.
Gastric emptying rate is faster in case of
solution and suspensions than solid and no
disintegrating dosage forms. Similarly, a long
intestinal transit time is desirable for complete
absorption of drug, e.g., for enteric coated
formulation and for drugs absorbed from
specific sites in the intestine. Peristaltic
contraction promotes drug absorption by
increasing the drug membrane contact and by
enhancing dissolution especially of poorly
soluble drugs. Influenced by food, disease and
drugs, e.g., metoclopramide which promotes
intestinal transit and thus enhance absorption
of rapidly soluble drugs while anticholinergic
retards intestinal transit and promotes the
absorption of poorly soluble drugs [34–36].
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
Stereochemistry
Stereo
selectivity
is
anticipated
in
pharmacokinetics and/or pharmacodynamics.
A cost effective solution is available in the
market in the form racemate (Mixture of
stereoisomers) where one form may have
higher bioavailability than the other after oral
administration. Obviously use of in vitro
dissolution data of racemate will not be useful
in the development of IVIVC and hence
prediction of in vivo availability of active
enantiomer.
So
consideration
of
stereoisomerism in the development of IVIVC
may provide more meaningful relationship
[33, 37].
Solid Phase Characteristics
Solid phase characteristics of drug such as
amorphicity, crystallinity, hydration state and
polymorphic structures have significant
influence on dissolution rate [38]. Anhydrous
forms dissolve faster than hydrated form as
they are thermodynamically more active than
hydrates, e.g., Ampicillin anhydrate has faster
dissolution rate than trihydrate. Amorphous
forms of drug tend to dissolve faster than
crystalline materials [37], e.g., Novobiocin,
Griseofulvin, Phenobarbital, cortisone acetate
and chloramphenicol. However, dissolution
rate of amorphous erythromycin estolate is
markedly lower than the crystalline form of
erythromycin estolate. Particle size has also
significant influence [34].
IVIVC OF NOVEL DOSAGE FORMS
Enteric Coated Multiple Unit Dosage Form
An in vitro/in vivo relationship of a combined
multimechanistic dosage form has been
established using Wagner-Nelson mass
balance method in bagel dog using
theophylline as model drug [39]. Good
correlation (level A) was obtained for multiple
unit enteric coated granules by using
convolution method. The mean in vivo
dissolution profiles were predicted using
mathematical model of pellets' gastric
emptying. The dissolution tests were carried
out on a USP 4 - flow-through cell with enteric
coated pellets containing an acid-labile drug
and formulated as orodispersible tablets [40].
The in vitro dissolution and in vivo absorption
data for controlled-release microparticles of
tramadol hydrochloride was correlated with
the help of Wagner-Nelson method to establish
IVIVC [41].
Modified Oral Dosage Unit
Elementary osmotic pump tablet (EOPT) of
captopril was nurtured where drug release was
found to be affected by the amount of NaCl,
HPMCK15, and MCC in the core, and the
amount of PEG 400 in the coating solution.
EOPT showed a good correlation between
absorption in vivo and drug release in vitro
[42]. Fast and Slow release gliclazide
formulations were investigated for an IVIVC
using curve fitting analysis [43]. Ostrowski et
al. established Level A IVIVC for an
amoxicillin dispersible tablet [44]. One
reference and two test formulations based
IVIVC model was developed for different
clarithromycin granular suspensions using
wagner-Nelson deconvolution method [45].
Parenteral Controlled or Sustained Release
Drug Delivery System
Sample and separate, flow through cell and
dialysis technique are the methods for in vitro
drug release study of microparticles system for
parenteral administration [7, 32]. IVIVC can
be developed for parenteral dosage forms,
such as controlled-release particulate systems,
implants,
etc.
Sophisticated
modeling
techniques are needed to correlate the in vitro
and in vivo data, in case of burst release which
is unpredictable and unavoidable [46]. level B
correlation has been established for buserelin
implant where the in vitro and in vivo data
were analyzed using model-independent and
model-dependent methods [47]. IVIVC was
investigated between the sodium diatrizoate
(DTZ) disappearance profile obtained from the
donor compartment of the rotating dialysis cell
model and the joint disappearance profile
following intra-articular administration [48].
The potency of the Cuban Hepatitis B Vaccine
was ascertained by an in vitro assay for quality
control through its correlation with the in vivo
potency. The results revealed a correlation
coefficient of 0.87 and 100% coincidence in
complying with the specification [49]. A level
A correlation was established for the
biodegradable parenteral formulation with
predominant diffusion controlled release while
those where drug release occurred by a
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(IVIVC): A Strategic Tool in Drug Product Development
combination of diffusion and erosion
processes, level B correlation was achieved
[9].
Bioadhesive Tablets and Film
Rivastigmine, an anti-Alzheimer's drug has
low oral bioavailability and severe GI adverse
effects. Excellent buccal bioadhesion and
transmucosal permeation has been reported for
rivastigmine buccal film. IVIVC was
established using wegnor nelson method with
in vivo studies carried out in rabbits [50]. A
significant in vivo in vitro correlation (IVIVC)
was established between the in vivo residence
time in the buccal cavity and the in vitro
bending point obtained from the dissolution
data for a buccal tablet [51]. Successful IVIVC
was achieved for ketamine and piroxicam [52].
Transdermal Drug Delivery System
USP 29 gives methods for in vitro drug release
testing of transdermal patches like paddle over
disk, cylinder method and reciprocating disk
method. But Franz diffusion cell are highly
used for this purpose [37]. A reservoir-type
transdermal delivery system (TDS) of bufalin
was investigated for IVIVC. An in vitro-in
vivo correlation (IVIVC) enabled the
prediction of pharmacokinetic profile of
bufalin from in vitro permeation results using
deconvulation procedure [53].
Nasal Drug Delivery System
Drugs are given by nasal route for both local
and systemic applications. Variety of methods
on in vitro testing of nasal drug delivery
system like emitted dose, droplet or particle
size distribution, spray pattern and plume
geometry are available [37]. FDA guidance
recommends these methods as a means of
documenting
bioavailability
and
bioinequivalence for topically acting solution
formulations, because they can be performed
reproducibly and are more discriminating
among products. Gamma scintigraphy and
three-dimensional method of positron emission
tomography (PET) have been widely utilized
for development of IVIVC at the same time
reduction in use of animals [54].
Colonic Drug Delivery System
Crohn’s disease or chronic inflammatory
colitis may be more effectively treated by
direct drug delivery to the colon. An attempt is
Chavda et al.
being made for in vitro/in vivo correlation
(IVIVC) of 5-FU film-coated colon-targeted
pellets in dogs which has provided good linear
regression relationship between the percent in
vitro dissolution in simulated colonic fluid and
the percent absorption or percent AUC [55].
BioDis method was used to establish a
physiologically relevant IVIVC for two
prototypes using a prospective in vitro study
using caffeine as model drug [56].
Suppositories
Either for local or systemic drug delivery can
be achieved using this system. Modified
basket or paddle methods are recommended
for lipophilic suppositories while conventional
basket, paddle or flow-through cells are
recommended for hydrophilic suppositories
[37]. Three different suppository formulations
of indomethacin were utilized to develop
IVIVC using wegnor-nelson method [57].
Microsphere
An in vitro-in vivo correlation of sustained
release
lamivudine
microspheres
was
established after administering orally to New
Zealand white rabbit species [58]. The IVIVC
for microsphere was established by
comparison of cumulative absorption profile
and cumulative in vitro dissolution profile, In
vitro dissolution rate constant (K) versus AUC
(good linear correlation), Mean dissolution
time versus mean residence time. An in
vitro/in vivo correlation (IVIVC) of huperzine
A loaded poly(lactic-co-glycolic acid) (PLGA)
microspheres was established by injecting
intramuscularly (i.m.) or subcutaneously (s.c.)
to five beagle dogs. The linear relationship
was better in the case of I.V use and the values
of correlation coefficient were higher when
particles are smaller [59]. An in vitro/in vivo
evaluation of microparticle formulations
containing meloxicam has been done by a
model independent deconvolution approach
[60]. Similarly, an in vitro-in vivo relationship
of controlled-release microparticles loaded
with tramadol hydrochloride has been
established using Wagner-Nelson method [61].
Self-emulsifying Drug Delivery Systems
The absorption study of probucol simulated
using dynamic lipolysis model from three
lipid-based formulations and to predict the in
vitro–in vivo correlation (IVIVC) using neuro-
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
fuzzy networks [62]. The rate and extent of
drug release from the oil formulation were
found to be significantly lower than from
SMEDDS and SNEDDS. The employed
neuro-fuzzy model (AFM-IVIVC) achieved
significantly high prediction ability for
different data formations (correlation greater
than 0.91 and prediction error close to zero),
without employing complex configurations.
Self -nanoemulsifying Systems of Carvedilol
was successfully developed.
Level A IVIVC was established for it where
percent drug absorbed data at various time
points were obtained using modified WagnerNelson method and correlated with percent
drug release data [63].
IVIVC for Liposomes and Other Targeted
Vesicular Delivery
An in vitro assay based on surface plasmon
resonance (SPR) was utilized to predict the in
vivo circulation kinetics of PEGylated
liposomes which is an opsonizaton reaction
[64]. With SPR it is possible to measure the
binding of drug carriers to a coated surface, in
realtime, under dynamic conditions and
without the interrupting washing steps hence
the extent of protein binding could be
correlated with the clearance of liposome.
APPLICATIONS
The use in vitro dissolution study in lieu of
human bioequivalence studies which will
reduce the number of human bioequivalence
studies during initial approval process as well
as certain scale up and post approval changes
is the adjudicate the IVIVC.
Manufacturing Control
Manufacturing process management (MPM) is
a collection of technologies and methods used
to define how products are to be manufactured.
In certain cases, especially for ER
formulations, the dissolution test can serve not
only as a quality control for the manufacturing
process but also as an indicator of how the
formulation will perform in vivo
[3]. The extended release products are
distinguished through their input rate to the
absorption site. Therefore, the rate of drug
release from these products is an important
feature and should be carefully controlled and
evaluated. The in vitro dissolution/release test
is meaningful only when the test results are
correlated to the products’ in vivo
performances [7, 32]. The ultimate goal is to
assure consistent safety and efficacy
performance for the marketed product relative
to those for the clinical trial formulation.
Nanoparticles
An in vitro/in vivo correlations (IVIVCs) have
been established for a sustain release
formulation of silybin (72 h) using a
combination of solid dispersion, gel matrix
and porous silica nanoparticles (PSNs) [66].
Process Change Assurance
The regulatory agencies are more stringent for
not only new drug approval but also for
manufacturing processes of approved products
and certain post approval changes, one has to
demonstrate that kind of change, even an
engineering improvement, does not cause
changes in the finished product’s in vivo
performance. Consequently, many changes
have to be supported by a bioequivalence
study. With Level A correlation a
bioequivalence study should no longer be
necessary. In such cases, the scientists and
regulatory agencies may consider a pilot
pharmacokinetic study as an assurance that the
new excipient does not inadvertently affect the
absorption [7, 9]. IVIVC development should
be planned a priori instead of being a post-hoc
event.
A correlative model to predict in vivo AUC for
nanosystem drug delivery with release ratelimited absorption was developed [67].
Dissolution/Release Rate Specifications
Without a correlation, the specifications of an
in vitro test can be established only
Since this SPR based assay enables rapid and
extensive screening of various different types
of liposomes and other particulate drug
carriers, it is expected to have significant
impact in the study of in vivo properties of
various drug delivery systems. Noninvasive
positron emission tomography (PET) imaging
can also be used for the same purpose. The
target tissue concentrations can be predicted,
e.g., in the brain, from in vitro release
experiments using PET [65].
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(IVIVC): A Strategic Tool in Drug Product Development
empirically. This approach is data driven but is
valid only if all the batches have been
extensively evaluated in clinical trials;
furthermore, it probably can detect only
relatively large differences between different
batches. It is therefore, more precise to set up
the specification using the correlation to
evaluate the in vivo consequences of the range.
Clearly, the pharmacokinetic consequences
alone are not sufficient to set up the
specifications.
The
pharmacodynamics
knowledge is the key to make the specification
clinically meaningful.
In the absence of the information, some
scientists may be willing to rely on the
empirical bioequivalence range of ±20% as the
first guidance. In case of a one-to-one
correlation, this automatically translates in a
dissolution rate change of ±20%. It is
empirically derived dissolution range is much
wider than ±20%, and then the companies
invariably believe that the products have been
punished by the presence of one-to-one
correlation. Modified-release dosage forms
typically require dissolution testing over
multiple time points, and IVIVC plays an
important role in setting these specifications.
Specification time points are usually chosen in
the early, middle, and late stages of the
dissolution profiles. In the absence of an
IVIVC, the range of the dissolution
specification rarely exceeds ± 10% of the
dissolution of the pivotal clinical batch.
However, in the presence of IVIVC, wider
specifications may be applicable based on the
predicted concentration-time profiles of test
batches being bioequivalent to the reference
batch. The process of setting dissolution
specifications in the presence of an IVIVC
starts by obtaining the reference (pivotal
clinical batch) dissolution profile. The
dissolution of batches with different
dissolution properties (slowest and fastest
batches included) should be used along with
the IVIVC model, and prediction of the
concentration time profiles should be made
using an appropriate convolution method.
Specifications should optimally be established
such that all batches with dissolution profiles
between the fastest and slowest batches are
bioequivalent and less optimally bioequivalent
to the reference batch.
Chavda et al.
Early Development of Drug Product and
Optimization
Any toxicity and efficacy of a drug product
should be characterized by in vivo and in vitro
studies [9]. Consistent safety and efficacy
profiles for the marketed product relative to
those for the clinical trial formulation is of
keen interest in the life cycle of drug
development During this stage, exploring the
relationship between in vitro and in vivo
properties of the drug in animal models
provide an idea about the feasibility of the
drug delivery system for a given drug. Plasma
drug concentrations are identified as the most
successful surrogate for safety and efficacy.
Validated models can provide the means for
predicting/determining the clinical impact of
changes without the need for additional in vivo
studies.
Formulation Assessment
It is particularly of a much interest that a
dissolution method utilized should correlate
the performance of formulations with different
release rate in product development.
Depending on the nature of the correlation,
further changes to the dissolution method can
be made. When the discriminatory in vitro
method is validated, further formulation
development can be relied on the in vitro
dissolution only. Setting the clinically relevant
specifications starts with the development of a
clinically relevant (predictive) dissolution
method and dissolution acceptance criterion
which will establish a relationship between
dissolution and bioavailability with limited
regulatory flexibility.
Biowaiver for Minor Formulation
To waive bioequivalence requirements for
lower strengths of a dosage form justify the
IVIVC. It reduces development time and
optimizes the formulation. A clinically
relevant dissolution specification is possible
with the current conventional dissolution
methods. Drug development requires changes
in formulations due to a variety of reasons,
such as unexpected problems in stability,
development, availability of better materials,
better processing results, etc. Having an
established
IVIVC
can
help
avoid
bioequivalence studies by using the dissolution
profile from the changed formulation, and
subsequently predicting the in vivo
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Page 48
Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
concentration-time profile. This predicted
profile could act as a surrogate of the in vivo
bioequivalence study [68]. The nature of postapproval changes could range from minor
(such as a change in nonrelease-controlling
excipient) to major (such as site change,
equipment change, or change in method of
manufacture, etc.) [69].
Concept of Mapping
Critical Manufacturing Variables (CMV) are
those which ultimately affect drug release
from the product. Mapping is the process
where CMV are correlated with obtained in
vitro and in vivo data so as to define the
boundaries of in vitro dissolution profiles on
the basis of acceptable bioequivalency criteria.
As a consequence of this clairvoyance on
product specifications with acceptable
dissolution specifications are evitable and
desirable product performance with continuous
assurance and predictability is obtained [9].
Validated models can provide the means for
predicting/determining the clinical impact of
CMV changes without the need for additional
in vivo studies.
LIMITATIONS OF IVIVC
1. The drug dissolution design is not able to
solve the issues related to complex drug
absorption process.
2. Food has the direct influence on
formulation behavior.
3. In the deconvolution procedure more than
one dosage form is needed and if possible
intravenous injection or solution.
4. The drug release must depend on the
formulation, and must be the slowest
phenomenon as compared to dissolution
and absorption.
5. It is very difficult to establish IVIVC for
nonlinear pharmacokinetics arising due to
active absorption. First pass or metabolic
process.
6. Typically regulatory guidance require
IVIVC to be conducted in fasted state, is it
necessary for a compound with a label
requirement to take it with food?
7. IVIVC for immediate release dosage form
especially for BCS II drugs is difficult as
different particle size to achieve different
dissolution rates.
REGULATORY PERSPECTIVE
OF IVIVC
The regulatory agencies as well as
industrialists set their thinking regarding
IVIVC especially for extended release dosage
forms. This predictive relationship between in
vitro dissolution and the in vivo bioavailability
has just decrease the regulatory burden at the
same time acquaint good product quality in
terms of developmental and evaluatory
attributes [70]. For the bioequivalence
estimation the predictability of dissolution test
for solid oral dosage forms weather it is
quality of product or clinical performance has
provide an idea and confidence to used it as
surrogate
tool
for
bioequivalence
establishments [71]. USFDA has provided a
guidance for industry for modified release
dosage form regarding Application of IVIVC
and its feasibility in the establishment [3]. For
the immediate release dosage forms; this
concept is very difficult to digest and are not
covered under this as dissolution for them is
not rate limiting step. It has brought simplicity
in manufacturing with cogent dissolution
specifications. IVIVC for the nonoral products
is very difficult to develop admirable
dissolution methods. This is a expected and
glowing area to aided some sincere efforts to
be transformed to predictive dissolution
methodologies [72].
IVIVR
One possible substitution for IVIVC is IVIVR,
with "R" denoting "relationship." By
comparison with Level A IVIVC, IVIVR
analysis would concern the elucidation of the
in vitro dissolution - in vivo absorption
relationship. Hence, IVIVR need not be
limited to straight-line relationships, which
appear to be generally incorrect for IR
products. One intent of IVIVR should be to
learn about the relative contribution of
dissolution to a product's overall absorption
kinetics.
One model for IVIVR is:
Where, Fa is the fraction of the total amount of
drug absorbed at time t, fa is the fraction of the
dose absorbed at t = #,
α is the ratio of the apparent first-order
RRJoDFDP (2016) 31-54 © STM Journals 2016. All Rights Reserved
Page 49
(IVIVC): A Strategic Tool in Drug Product Development
Chavda et al.
permeation rate constant (kpaap) to the firstorder dissolution rate constant (kd), and Fd is
the fraction of drug dose dissolved at time t.
Of note is that the Level A method is a special
(linear) case of Eq. (1). If fa = 1.0, (i.e.,
complete absorption) and α >>1#, (i.e.,
strongly dissolution rate-limited absorption),
then Fa = Fd, as in Figure 1.
distribution, is more appropriate for general
survey or prediction, numerical algorithms are
useful for treating actual experimental data.
Deconvolution is not considered an algorithm
by its own, but the inversion of a
corresponding convolution. MS Excel and
other relevant statistical software’s are very
useful tool for all these applications [77].
This IVIVR analysis has been applied to
several formulations of metoprolol, piroxicam,
and ranitidine. IVIVR analysis indicated that
formulation properties and drug substance
biopharmaceutic properties influenced the
degree to which dissolution controlled overall
absorption kinetics. Interestingly, dissolution
was not rate-limiting from even the slowest
dissolving IR formulations for the high
solubility drugs.
FUTURE DIRECTIONS
Handling of Computational in vitro/in vivo
Correlation Problems by Microsoft Excel
Most computations in the field of in vitro/in
vivo correlations can be handled directly by
Excel worksheets, without the need for
specialized
software.
Excel
features,
applications are used for numerical
computation of AUC and Mean, Wagner–
Nelson and Loo–Riegelman absorption plots,
and polyexponential curve fitting [73]. With
regard to computer software, SAS [8] with its
interactive matrix language (IML) is deemed
the most professional tool for general
computations. Packages such as WinNonlin or
Kinetika are specifically designed to handle
pharmacokinetic tasks. But also there, many
standard IVIVC tasks are not covered and
must be programmed by the user [73–75]. MS
Excel is a useful tool to handle in vitro/in vivo
correlation (IVIVC) distribution functions,
with emphasis on the Weibull and the biexponential distribution, which are most useful
for the presentation of cumulative profiles,
e.g., release in vitro or urinary excretion in
vivo, and differential profiles such as the
plasma response in vivo [76].
The classical term in vitro-in vivo correlation
tools used to describe the relationship between
input and weighting/response in a linear
system, where convolution and deconvolution
are the output products to represent the drug
release in vitro. While functional treatment,
e.g., in terms of polyexponential or Weibull
The use of the term IVIVR rather than IVIVC
is preferred. Immediate release products are
amenable to dissolution-absorption analysis.
However, the term IVIVR itself is neither new,
nor fundamental. Rather, what is needed is a
better understanding of in vivo dissolution, and
it’s in vitro surrogate, the dissolution test.
Additionally, dissolution needs to be
considered in the context of other parallel and
sequential processes, (e.g., permeability,
degradation, and transit). Through a better
understanding of dissolution, dissolution and
IVIVR can facilitate not only SUPAC-type
changes, but also facilitate drug product
development.
CONCLUSIONS
The pharmaceutical industry has been striving
to find a ways to saving precious resources in
relevance to the budgets and increasing cost of
drug development. The only tool which can be
useful at the various stages of drug
development is IVIVC. It also plays an
important role around the regulatory bodies
around the world. IVIVC can serve as
surrogative tool for in vivo bioavailability and
to support biowaivers which allows setting the
dissolution specification and methods. The
substitute of expensive clinical trials with the
use of IVIVC is perhaps the most important
feature of IVIVC. Some of the scale-up and
postapproval changes are easily governed by
using the concept of IVIVC.
Basically it is used for the oral products; there
exists a need to develop methodologies and
standards for nonoral delivery systems, to
develop more meaningful dissolution and
permeation methods. The correlation-coefficient solely depends on the quality of the
data. As in vivo data are now well
standardized, the main effort must be directed
to the in vitro data. Various apparatus and
media should be tested and assessed in terms
RRJoDFDP (2016) 31-54 © STM Journals 2016. All Rights Reserved
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Research & Reviews: A Journal of Drug Formulation, Development and Production
Volume 3, Issue 3
ISSN: 2394-1944(online)
of their in vivo predictability. It is helpful for
the regulatory approach and many more things
to be predicted using the user who acquire the
in depth knowledge of the method and of the
confidence of its prediction.
13.
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Cite this Article
Vivek P. Chavda, Dhaval Shah, Hemal
Tandel et al. In Vitro–In Vivo
Correlation (IVIVC): A Strategic Tool
in Drug Product Development. Research
& Reviews: A Journal of Drug
Formulation,
Development
and
Production. 2016; 3(3): 31–54p.
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