REVIEW

Rate- and Extent-Limiting Factors of Oral Drug Absorption: Theory

and Applications
KIYOHIKO SUGANO, KATSUHIDE TERADA
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan
Received 18 December 2014; revised 23 January 2015; accepted 23 January 2015
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24391
ABSTRACT: The oral absorption of drugs has been represented by various concepts such as the absorption potential, the maximum
absorbable dose, the biopharmaceutics classification system, and in vitroin vivo correlation. The aim of this article is to provide an
overview of the theoretical relationships between these concepts. It shows how a simple analytical solution for the fraction of a dose
absorbed (Fa equation) can offer a theoretical base to tie together the various concepts, and discusses how this solution relates to the ratelimiting cases of oral drug absorption. The article introduces the Fa classification system as a framework in which all the above concepts
were included, and discusses its applications for food effect prediction, active pharmaceutical ingredient form selection, formulation
C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
design, and biowaiver strategy. 
Keywords: intestinal absorption; salt selection; bioequivalence; biopharmaceutics classification system (BCS); in silico modeling; dissolution; food effects; formulation; gastrointestinal transit; oral absorption

INTRODUCTION
The theories of oral drug absorption have been actively investigated in the last three decades.1 Various concepts have been introduced to represent the oral absorption of drugs, for example,
the absorption potential (AP),2 the maximum absorbable dose
(MAD),3 the biopharmaceutics classification system (BCS),4 the
developability classification system (DCS),5 and in vitroin vivo
correlation (IVIVC).6 These concepts originate from the same
differential equations that describe the dissolution and intestinal membrane permeation of drugs. The aim of this article is to
Abbreviations used: AP, absorption potential; API, active pharmaceutical ingredient; AUC, area under the curve; AUC BE, bioequivalence of AUC; BCS, biopharmaceutics classification system; BCS-BWS, BCS-based biowaiver scheme;
BE, bioequivalence; COAS, computational oral absorption simulation; Cmax BE,
bioequivalence of Cmax ; Cdissolv , concentration of a dissolved drug; Cdissolv,ss ,
concentration of a dissolved drug at the steady state; DCS, developability classification system; DF, degree of flatness; DRL, dissolution rate limited; Deff ,
effective diffusion coefficient; Dn, dissolution number; Dncrit , critical dissolution
number; Do, dose number; Docrit , critical dose number; Dose, dose strength; EIE,
equivalent-in-effect; EIP, equivalence of independent parameter; Fa, fraction of
a dose absorbed; FaCS, Fa classification system; GI, gastrointestinal; IR, immediate release; IVIVC, in vitroin vivo correlation; MAD, maximum absorbable
dose; MDT, mean dissolution time; PBPK, physiologically based pharmacokinetics; PL, permeability limited; PL-E, epithelial membrane permeability limited;
PL-U, unstirred water layer permeability limited; Pncrit , critical permeation
number; PUWL , unstirred water layer permeability; Papp , apparent permeability; Peff , effective intestinal membrane permeability; Pep , epithelial membrane
permeability of unbound drug molecules; PKs, pharmacokinetics; Pn, permeation number; S1I7, GI compartment model with one stomach compartment
and seven intestinal compartments; SL, solubilitypermeability limited; SL-E,
solubilityepithelial membrane permeability limited; SL-U, solubilityunstirred
water layer permeability limited; SMF, safe margin factor; Sblank , solubility in a
blank buffer; Sdissolv , solubility in the GI tract (free and bile micelle bound drug
molecules); Sn, saturation number; Tabs , transit time through the absorption
site in the GI tract; UWL, unstirred water layer; V, fluid volume in the GI tract;
VE, villi expansion factor; Xdissolv , dissolved amount; fu , free fraction at the
surface of the intestinal epithelial membrane; in vitro T85% , time to reach 85%
dissolution in an in vitro dissolution test; kabs , absorption rate coefficient; kdiss ,
dissolution rate coefficient; kel , elimination rate coefficient; kperm , permeation
rate coefficient; rp , particle radius of a drug; T1/2 , elimination half-life.
Correspondence to: Kiyohiko Sugano (Telephone: +81-47-472-1494; Fax: +8147-472-1337; E-mail: kiyohiko.sugano@phar.toho-u.ac.jp)
Journal of Pharmaceutical Sciences


C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association

provide a comprehensive overview of theoretical relationships

between these concepts. A brief history in this scientific area is
shown in Table 1.

DIFFERENTIAL EQUATIONS OF ORAL DRUG

ABSORPTION
The oral absorption of a drug can be expressed by the two differential equations that describe the dissolution and intestinal
membrane permeation of a drug (except for supersaturation).
The dissolution of a drug is usually expressed by the Noyes
Whitney equation introduced in 1897 (Eq. (1)).7,14 The intestinal membrane permeation of a drug is usually expressed by the
first order equation (Eq. (2)). These are typically expressed as:


1
2
X dissolv
dX undissolv
3
3
= kdiss Dose X undissolv 1
dt
Sdissolv V

(1)

dX abs
= kperm X dissolv
dt

(2)

kdiss =

3Deff Sdissolv
rp2 D

(3)

2DF
Peff
R

(4)

kperm =

where kdiss is the dissolution rate coefficient, kperm is the permeation rate coefficient, Dose is the dose strength, Xundissolv is
the undissolved amount, Xdissolv is the dissolved amount, Xabs
is the absorbed amount, Sdissolv is the solubility in the intestinal fluid (free and bile micelle bound drug molecules), Deff is
the effective diffusion coefficient, Peff is the effective intestinal membrane permeability (free and bile micelle bound drug
Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

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Table 1. Brief History of Theoretical Biopharmaceutics

Year

Events

Reference

1897
1985
1986
1993
1995
1996

NoyesWhitney equation
Absorption potential
Mixed tank model
Plug-low model
Biopharmaceutics classification system
Maximum absorbable dose
Compartment absorption transit model
Absorption-limiting step classification
Biopharmaceutics drug disposition
classification system
Fa equation
Developablility classification system

7
2
8
9
4
3
10
11
12

1999
2005
2009
2010



Fa = 1 exp kperm Tabs = 1 exp (Pn)

13
5

Sequential First-Order Approximation

QUEST FOR ANSWERS: A BRIEF HISTORY

Trivial Answers
Dissolution Rate-Limited Cases
In the case of dissolution rate-limited (DRL) absorption, Fa
can be calculated by integrating the dissolution equation. By
applying Xdissolv = 0 (perfect sink condition), we obtain
 32

2
= 1 1 Dn
3

(5)

(6)

Permeability Limited Cases

When the whole amount of a drug instantly and completely
dissolves after administration in the GI tract, the dissolution
process will not become the rate-limiting step. In this case, the
Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

Fa = 1

kperm
exp (kdiss Tabs )
kperm kdiss



Pn
kdiss
exp (Dn)
exp kperm Tabs = 1
kdiss kperm
Pn Dn

Dn
exp (Pn)
Dn Pn

(8)

The above three trivial answers were simply derived from

the differential equations. However, the concentration gradient term [1Xdissolv /(Sdissolv V)] makes it difficult to solve the
equations for the cases of great interest in the pharmaceutical sciences. As no trivial answer is provided for this case,
pharmaceutical insights are required to solve the equations.
The concept of solubility - permeability limited absorption first
emerged as the AP in 1985,2 and then eventually developed
to the concept of the MAD3 and BCS.4 When the dissolution
rate of a drug is much faster than the permeation rate and
the dose to solubility ratio (Dose/Sdissolv ) exceeds the intestinal
fluid volume (V), the concentration of a dissolved drug (Cdissolv =
Xdissolv /V) in the GI tract reaches close to the equilibrium solubility of the drug (Sdissolv ). In this case, Eq. (2) can be integrated
by applying a constant value of Xdissolv = Sdissolv V as:

 32

where Tabs is the transit time through the absorption site in

the GI tract. Tabs can be approximated as the small intestinal
transit time for many cases. We can introduce a dimensionless
parameter for dissolution [dissolution number (Dn) = kdiss
Tabs ]. This equation can be approximated as a first-order process,
Fa = 1 exp (kdiss Tabs ) = 1 exp (Dn)

When the oral absorption of a drug can be represented as the

sequential first-order process of dissolution and permeation,
the analytical solution becomes

Solubility - Permeability Limited Case

A simple analytical solution can usually be derived from a

differential equation(s) by applying the initial and boundary
conditions for a special (limiting) case. Historically, this approach was first applied to the dissolution and permeation
equations for the three absorption limiting cases, that is, the
dissolution rate, permeability, and solubilitypermeability limited (SL) cases. An illustrative explanation of these limiting
cases is available elsewhere in the literature.15

2
Fa = 1 1 kdiss Tabs
3

(7)

This equation is often used to correlate in vitro membrane permeability values with Fa, for example, the Caco-2
cell assay,16,17 the MadinDarby canine kidney cell assay,18
and the parallel artificial membrane permeation assay.1921 We
can also introduce a dimensionless parameter for permeation
(Pn = kperm Tabs ).

molecules), D is the true density, and rp is the particle radius

of a drug. R is the radius of the gastrointestinal (GI) tract, DF
is the degree of flatness, and V is the fluid volume in the GI
tract. Eq. (1) is for monodispersed spherical particles smaller
than 60 :m. To calculate the fraction of a dose absorbed (Fa),
Eqs. (1) and (2) have to be integrated simultaneously. However,
the exact analytical solution for general cases has not been discovered. The quest for the answer(s) that leads to Fa is one of
the main themes of theoretical biopharmaceutics.

oral absorption of the drug becomes permeability limited (PL).

The trivial answer for Eq. (2) is:

Fa =

MAD
Pn
kperm Sdissolv VTabs
=
=
Dose
Dose
Do

(9)

Dose
Sdissolv V

(10)

Do =

where Do is the dose number. This oral absorption pattern is

often referred as solubility limited in the literature. However,
to explicitly recognize the role of permeability, we refer it as
solubility - permeability limited in this article. In the AP, kperm
is represented by the lipophilicity of a drug. The maximum
absorbable dose is defined as MAD = kperm Sdissolv V
Tabs . BCS categorizes a drug by Do and Pn. The classification
boundary of DCS is based on Fa = Pn/Do (Fig. 1). Therefore,
AP, MAD, BCS, and DCS are related to each other via Eq. (9).
DOI 10.1002/jps.24391

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Computational Numerical Integration

Pn
BCS I

BCS II

10

0.1

10
Do

BCS III

BCS IV

0.1
Figure 1. The BCS plane (PnDo plane) and DCS lines. The solid and
gray lines corresponds to Fa = Pn/Do = 0.3 and 0.7 for SL cases.

Approximate Fa Equation for General Cases

In 2009, by applying the steady-state approximation, an approximate open analytical solution for Fa was discovered.13,22
This equation (the Fa equation, Eq. (11)) captures the essential
processes of oral drug absorption (except for supersaturation).


1
Fa = 1 exp 1 Do
+ Pn
Dn

1
1
+ Do
Dn
Pn


if Do < 1, set Do = 1.

for Fa < 0.7

(11)

By taking the limit, the Fa equation can be rearranged to

Eqs. (6), (7) and (9). When comparing Eq. (11) with Eq. (7), we
can define the absorption rate coefficient (kabs ) as:
1
Do
1
=
+
kabs
kdiss
kperm

(12)

Some important aspects of Fa can be directly derived by the

Fa equation.

r Fa is determined by three factors, i.e., Dn, Do, and Pn.

r Dn is independent from Do and Pn.
r Pn and Do are conjugated as Pn/Do.
r Dn or Pn/Do can be the dominant factor when one largely
exceeds the other.
The Fa equation enables us to predict Fa from the in vitro
data available in drug discovery by a back-of-the-envelope
calculation.23 The saturation number (Sn) that represents the
ratio of Cdissolv at a steady state (Cdissolv,ss ) and Sdissolv can be
defined as:
Sn =

DOI 10.1002/jps.24391

1
Cdissolv,ss
=
Pn
Sdissolv
1 + DnDo

(13)

The wide spread of personal computers after the late 1980s provided new research tools for many scientists. Computational
numerical integration of differential equations (computer simulation) can provide answers to more general cases compared
with analytical solutions. Computer simulation is now used in
various research areas such as astronomy, meteorology, engineering, economics, and so on. Pharmaceutical sciences have
been reaping many benefits from computer simulation as well.
Computational oral absorption simulations (COASs)13 have
been used since the mid-1980s. A simple mixed tank model
and a plug flow model were first employed to represent the
GI tract.8,9 The dissolution and permeation equations were numerically integrated with these models. The compartment absorption transit model was then introduced in 1996 to represent the distribution of a drug in the GI tract.10,11,24 The other
multicompartment models such as the gastrointestinal transit
absorption model25 and the advanced dissolution absorption
and metabolism model26 were later introduced. In most cases,
the stomach and the small intestine are expressed as one and
seven compartments, respectively [the GI compartment model
with one stomach compartment and seven intestinal compartments (S1I7) model]. In each GI compartment, the dissolution
and permeation processes of a drug are simulated. The GI transit of polydispersed particles between the compartments can be
simultaneously simulated.13 By using a S1I7 model, various
scenarios of oral drug absorption can be simulated, such as the
effects of pH change in the GI tract.27
One of the well-known disadvantages of computational simulation is that it might distract us from understanding the
deep and often abstracted nature.28 Therefore, even in this age
of massive computing power, analytical solutions will not lose
their importance. Computer simulation and analytical solution
are complementary to each other. Because of its complexity,
COAS is often used as a black box. However, commercial programs have not been sophisticated enough for nonexpert users.
Therefore, a simple analytical solution and/or a classification
system should be used alongside with COAS to understand the
essence of oral drug absorption. Commercial COAS programs
are often used side by side with a physiologically based pharmacokinetics (PBPK) model.29,30 Pharmacokinetic (PK) scientists sometimes use oral absorption and formulation modules in
software, whereas formulation scientists merely use the PBPK
module on its own. A good collaboration between the biopharmaceutics and PK scientists is vital for an appropriate use of
COAS. Even though the S1I7 models seem to provide significant advantages, a simple one compartment model is sufficient to predict Fa in many cases.31 The Fa equation and the
seven compartment model give similar Fa values for nonsupersaturable cases.22 To simulate the plasma concentrationtime
profile of a drug, kabs can be used with a one-compartment PK
model.
As COAS is a relatively new research tool for pharmaceutical
scientists, there is little consensus on how to write the method
section in a research paper. There are many indefinite factors
in in vivo GI physiology and there are significant discrepancies
between in vitro and in vivo conditions. The awareness of this
issue initiated an international project in Europe (OrBiTo).32
Therefore, an almost perfect prediction of PK profiles reported
so far in many articles is at least questionable (many of them
employ a commercial software). A good simulation practice13
Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

REVIEW

Figure 2. Fa classification system and its relationship with BCS, food effect (by bile micelles), API and formulation design, and biowaiver
strategy.

should be provided as a guidance for the healthy development

of this emerging scientific area.

BIOPHARMACEUTICS CLASSIFICATION SYSTEM

The biopharmaceutics classification system has been widely
used in drug discovery and development. BCS was derived from
Eqs. (1) and (2) by Amidon and coworkers4,9 in the mid-1990s.
BCS classifies a drug substance by Do and Pn. A drug can be
spotted on the DoPn plane (Fig. 1). BCS was originally introduced for biowaiver consideration. However, as a simple and
basic classification system, BCS has inspired many scientists
to investigate its applicability to various situations in drug discovery and development. Roughly speaking, Do = 1 and Pn = 2
(Fa = 0.850.9) have been used as the criteria for solubility
and permeability, respectively. However, the rationale for the
high/low-permeability boundary has not been rigorously established. It might have been derived from the bioequivalence (BE)
criteria in the biowaiver scheme (discussed later), or indefinitely derived from the tacit knowledge among the experts.33
The biopharmaceutics drug disposition classification system
suggests that the extent of metabolism can be used as a surrogate for Fa.12,34
The Developability classification system also classifies a
drug by Do and Pn; however, the criteria are based on Fa =
Pn/Do rather than Do = 1 and Pn = 2 (Fig. 1).5 DCS can be
considered as an improved descendant of MAD that has also
been widely used in drug discovery and development (cf. Pn/Do
= MAD/Dose).35

FA CLASSIFICATION SYSTEM
The Fa equation can provide a classification system for oral
drug absorption (referred as the Fa classification system (FaCS)
in this article). FaCS includes the concept of BCS, but it provides a more mutually exclusive and collectively exhaustive
classification system for oral drug absorption (Fig. 2; Table 2).
On the basis of the Fa equation, the limiting factors of oral drug
absorption can be classified as:

r Dissolution rate limited (DRL)

r Permeability limited (PL)
r Solubility - permeability limited (SL)
The basic concept of this classification system might have
been implicitly suggested in the literature before the mid-1990s
or earlier. In 1999, Yu11 explicitly explained this concept with
the criteria shown in Table 2. Takano et al.36 experimentally
confirmed this concept.
Fa classification system and the criteria based on the Fa
equation were introduced in 2010 and 2011, respectively.23,37 In
FaCS, PL and SL can be further classified by the rate-limiting
factors of intestinal membrane permeation, i.e., the unstirred
water layer (UWL) and the epithelial membrane.38,39 The Peff
can be expressed as:
Peff =

1
PUWL

PE
+ VEf1u Pep

(14)

Table 2. Absorption-Limiting Steps in Oral Drug Absorption

Criteria
Absorption-Limiting Steps
Dissolution rate limited

Permeability limited

Solubilitypermeability limited

a
b

Yua

FaCS

Dn < 1.1
Pn > 5.7
Pn/Do >> 1
Dn > 4.4
Pn < 5.7
Pn/Do >> 1
Dn > 4.4
Pn > 5.7
Pn/Do << 1

Dn < Pn/Do

Fa = 1exp(Dn)

Pn < Dnb
Do < 1

Fa = 1exp(Pn)

Pn/Do < Dnb

Do > 1

Fa = Pn/Do

Fa Equation

Ref. 11. Converted to corresponding dimensionless numbers.

Further classified by the rate-limiting step of the effective permeability.

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DOI 10.1002/jps.24391

REVIEW

where PE is the plica expansion factor, VE is the villi expansion factor, fu is the free fraction at the surface of the intestinal
epithelial membrane, PUWL is the unstirred water layer permeability (free and bile micelle bound drug molecules), and
Pep is the epithelial membrane permeability of unbound drug
molecules. Taken together, FaCS classifies drug products into
the five classes as shown in Figure 2.23,37 FaCS explicitly includes the basic concept of BCS (classification by Pn and Do).
In addition, FaCS also explicitly includes the dissolution perspective as represented by the Dn in its classification scheme
(Fig. 2; Table 2). In contrast to commonly speculated interpretation, BCS cannot determine whether Fa becomes DRL
or not.5 For example, when the solubility of a drug is 0.001
mg/mL, the dose is 0.1 mg, the particle size is 20 :m, Deff
is 6.6 106 cm2 /s, and Peff is 6.6 104 cm/s (corresponding to BCS class I; Dn = 0.7, Pn = 18.9, Do = 0.8), Fa becomes DRL. The third discriminate point of FaCS is related
to the permeability criterion. Unlike BCS, the permeability
boundary in FaCS is based on the rate-limiting factors of intestinal membrane permeation, i.e., UWL or the epithelial
membrane.

FOOD EFFECT PREDICTION

The Fa equation and FaCS have been applied to elucidate the
food effect by bile micelles.37,40 In the DRL cases, the solubilization of a drug by bile micelles would increase the dissolution rate, leading to a positive food effect. For example, a
positive food effect (2.6-fold) was observed in ivermectin.41 In
the epithelial membrane permeability limited (PL-E) cases, a
negative food effect can be observed. Bile micelle binding reduces the unbound drug concentration at the epithelial surface and reduces the effective permeability of a drug.4244
In the solubilityepithelial membrane permeability limited
(SL-E) cases, Fa would not be increased by bile micelles. The
drug molecules bound to bile micelles cannot permeate across
the epithelial cell membranes. Therefore, the flux across the epithelial membrane would not be increased (flux = Sdissolv Peff
(Sblank /fu ) (VE fu Pep ) = Sblank VE Pep . Solubility in a
blank buffer (Sblank ) = Sdissolv fu ). Pranlukast was suggested to
be a typical example for this case.37 The solubility of pranlukast
was increased by approximately ninefold in the fed-state simulated intestinal fluid compared with that in the fasted state simulated intestinal fluid.45 However, area under the curve (AUC)
increased only 1.5-fold when taken with a food (cf. Fa% in the
fed state is 11% at 300 mg). In the solubilityunstirred water
layer permeability limited (SL-U) cases, a positive food effect
would be observed as the drug molecules bound to bile micelles
could permeate across UWL. Many drugs in this class show
positive food effects,46 for example, griseofulvin,47 danazol,48
and atovaquone.49

ACTIVE PHARMACEUTICAL INGREDIENT FORM

SELECTION AND FORMULATION DESIGN
Fa classification system can be used as a guidance for active
pharmaceutical ingredient (API) form selection and formulation design, which are critically important for successful drug
development.5,50,51
DOI 10.1002/jps.24391

DRL Cases
In the case of DRL, particle size reduction would be effective
to increase Fa. However, as the dissolution rate increases, the
absorption regime changes from DRL to SL. The critical particle radius to become DRL can be calculated based on the Fa
equation.23 The discriminate equation between DRL and SL is:
Dn <

Pn
Do

(15)

When the dimensionless numbers are broken down, this

equation becomes:
Sdissolv VSI 2DFPeff
3Deff Sdissolv
<
rp2 D
Dose
RSI

(16)

Sdissolv can be cancelled out from both sides of Eq. (16), suggesting that the discrimination boundary between DRL and SL
does not depend on the solubility of a drug (for Do > 1). Even
though it is counterintuitive, this can be interpreted as follows;
when Sdissolv is low, the dissolution rate becomes slow, and at the
same time, the ceiling of Cdissolv (i.e., Sdissolv ) becomes low. On
the contrary, when the solubility is high, the dissolution rate
becomes fast and the ceiling of Cdissolv becomes high. Therefore,
the tendency of Cdissolv to reach Sdissolv does not depend on Sdissolv
(cf. the Sn does not depend on Sdissolv as well). By solving this
equation for rp , we obtain23

rp >

3Deff DoseRSI
2DFPeff VSI

(17)

By using a conventional milling method, the mean particle

size can be reduced to 10 :m or less. Therefore, according to
Eq. (17), even for relatively high Peff cases (e.g., 5 104 cm/s),
when the dose is more than 20 mg, Fa becomes SL.
SL-E Cases
Theoretically, the free drug concentration at the epithelial
membrane surface should be increased to achieve an increase
in Fa for the SL-E cases. Supersaturable API forms and formulation technologies would be effective in this case. Supersaturable API crystalline forms are salts,52 cocrystals,53 and
anhydrates.54,55 Solid dispersions and some of digestible selfemulsifying drug delivery systems can also be employed to increase the free drug concentration at the epithelial membrane
surface.5658 It should be noted that an in vitro permeability assay often underestimates the permeability of a highly lipophilic
drug (the octanol water distribution coefficient > 1.5).59,60 This
could result in misclassification of permeability (i.e., a BCS
class II drug can be falsely classified as a BCS class IV drug). As
the physicochemical principles of solubility and passive membrane permeability suggest,61,62 a genuine low-solubility/lowpermeability drug rarely exists.
SL-U Cases
In addition to the solubilization technologies for the SL-E cases,
formulation technologies that increase the apparent solubility
would be effective for the SL-U cases, such as cyclodextrin.63
Interestingly, particle size reduction has been shown to be effective in increasing Fa for the SL-U cases.64,65 The particle
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drifting effect has been hypothesized to explain this

phenomenon.66 It is well known that small particles can drift
into the UWL.67,68 In this case, the apparent thickness of UWL
can be reduced.

BIOEQUIVALENCE
Problem Statement
The equivalence of the PKs between two drug products containing the same drug molecule is called BE. Clinical BE is
defined as 20% acceptance range (80%125%) for the 90% confidence interval of the ratio between test and reference least
square means after log transformation of the PK parameters
of interest, Cmax , and AUC.69 If it is possible to allow waivers
of clinical BE studies based on the in vitro data (biowaiver),
it would be beneficial for both drug developers and patients.
However, an in vitro dissolution test is not an all-round tool
and only reflects a certain dimension of complicated in vivo
situations. Therefore, the problem statement for a biowaiver
scheme is when and under what conditions can waivers of
clinical studies be allowed?4
BCS-Based Biowaiver Scheme
The BCS-based biowaiver scheme (BCS-BWS) for oral
immediate-release (IR) dosage has been employed by US FDA,
EMA, WHO, and many other regulatory agents. There are
many excellent review articles regarding BCS-BWS.33 The rationale to allow biowaivers for BCS Class I drugs was described
as,
When the in vivo dissolution of an IR oral dosage form is
rapid in relation to gastric emptying, the rate and extent of
drug absorption is likely to be independent of drug dissolution. Therefore, similar to oral solutions, demonstration
of in vivo bioequivalence may not be necessary as long
as the inactive ingredients used in the dosage form do not
significantly affect the absorption of the active ingredient.
Thus, for BCS Class I (high solubility- high permeability)
drug substances, demonstration of rapid in vitro dissolution using the recommended test methods would provide
sufficient assurance of rapid in vivo dissolution, thereby
ensuring human in vivo bioequivalence.33
In BCS-BWS, the criterion for solubility is based on the solubility of an API in the plain buffers of the entire pH range in
the GI tract (e.g., pH 1.27.4). The criterion for permeability
is based on the permeability value for nearly complete absorption (e.g., Fa > 0.850.90) (there are some variations in each
regulatory guideline).
Discussion Based on FaCS
In this section, a biowaiver strategy is discussed based on FaCS.
As described above, the dissolution criteria in BCS-BWS is
based on the ratio of the dissolution rate and the gastric emptying rate. However, the gastric-emptying rate largely depends
on the phase of the migrating motor complexes, which are the
waves of the GI walls that sweep through the stomach and the
intestine in a regular cycle during a fasting state.70 In addition, the gastric emptying half time can be as short as 4 min
in a fasted state.71,72 Furthermore, the solubility of a drug in
Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

the small intestine was suggested to be sufficient to justify

biowaiver.73,74 Therefore, in the following discussion, the gastric emptying is assumed instant. The following discussion is
not intended to suggest any change of the current regulatory
biowaiver guidelines. A biowaiver strategy is not only used for
a regulatory purpose but also used for routine formulation researches. An in vitro dissolution test is routinely used as a
surrogate of in vivo oral absorption in drug development.
Fa Congruent Condition
On the basis of the Fa equation, the congruence of Fa can be
written as:
Fa (Dn1 , Do1 , Pn1 ) = Fa (Dn2 , Do2 , Pn2 )

(18)

where the subscript number indicates each formulation (e.g., 1,

reference formulation; 2, test formulation). For BE, Fa should
be equivalent at any time point (cf. Fa is essentially a function of
time even though it usually refers to the total absorbed amount
at an infinite time after dosing). Usually, the equivalence of Fa
is judged by the representative parameters for the rate and
extent of Fa.
Cmax1 (Dn1 , Do1 , Pn1 ) = Cmax2 (Dn2 , Do2 , Pn2 )

(19)

AUC1 (Dn1 , Do1 , Pn1 ) = AUC2 (Dn2 , Do2 , Pn2 )

(20)

There are two types of conditions to satisfy these equations: the equivalence of independent parameter (EIP) and
equivalent-in-effect (EIE) conditions. When Dn, Do, and Pn of
two formulations are identical, it is obvious that Cmax and AUC
become equivalent (Fig. 3a).
Dn1 = Dn2 , Do1 = Do2 , Pn1 = Pn2

(21)

We can also define the EIE condition in which AUC and Cmax
become insensitive to the independent parameters. In a certain
range, even when the independent parameters differed (i.e.,
Dn1 Dn2 , Do1 Do2 , and/or Pn1 Pn2 ), it could result in
the bioequivalence of Cmax (Cmax BE) and AUC (AUC BE). For
example, when Dn >> Pn, Do <1, and Pn > 2, AUC becomes
insensitive to the differences of these parameters within this
range (Fig. 3b).
Dn1 , Dn2 > Dncrit ; Do1 , Do2 < Docrit ; Pn1 , Pn2 > Pncrit

(22)

where the subscript crit indicates the critical values to satisfy

the EIE conditions.
Discriminate Points in FaCS for Bioequivalence
In FaCS, each discriminate point determines whether an EIE
condition is applicable or not.
Dn Discriminate Point. The first discriminate point in FaCS
is Dn versus Pn/Do (Fig. 2; Table 2). We can define the critical
dissolution number (Dncrit ) as the lowest Dn value that provides
the Cmax and AUC ratios of more than 0.8 against a solution
formulation.75 The worst-case scenario within this range is that
one of the two formulations shows instant dissolution, whereas
the other shows slowest dissolution in this range. When both
DOI 10.1002/jps.24391

REVIEW

(a)
Formulation 1

Fa

Formulation 2

Dn1

Pn1

Dn2

Do1

Pn2
Do2

1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

(b)
Insensitive

Pn
Figure 3. An illustration of (a) EIP and (b) EIE conditions for biowaiver.

Dn1 and Dn2 are larger than Dncrit , the dissolution rate does
not affect the bioequivalence of AUC and Cmax even when
Dn1 Dn2 (Dn1 and Dn2 become EIE). When Dn1 and/or
Dn2 are smaller than Dncrit , AUC and/or Cmax become sensitive
to Dn. In this case, the EIP, that is, Dn1 = Dn2, has to be proved.
For the Cmax BE, Dncrit can be roughly calculated as:
Dncrit >

1
Do
Pn

T1/2

(23)

ln2 Tabs

The elimination half-life (T1/2 ) was included as it affects Cmax

[cf. Cmax 1/(1 + kel /kabs ); kel is the elimination rate coefficient; for kabs , see Eq. (12)]. The multiplying number of four is
originated from the 80% threshold of BE.
For the AUC BE of a low-permeability drug, Dncrit can be
roughly calculated to be 5 as:
1
kperm (Tabs MDT)
=1
> 0.8
kperm Tabs
Dncrit

(24)

where MDT is the mean dissolution time. The Tabs MDT term
suggests that MDT reduces the time available for drug absorption.
Numerical integration can be used to calculate Dncrit more
accurately. Figure 4a shows the relationship among Pn, elimination T1/2 , and Dncrit obtained by numerically solving three
first-order equations (with kdiss , kperm , and kel ) that are sequentially connected (simulated for Tabs = 3.5 h; Do < 1).
Figure 4a suggests that in the case of short half-life
drugs (<120 min.), the dissolution rate criteria for a highpermeability drug should be larger than that for a lowpermeability drug because of the sensitivity of Cmax to Dncrit .75,76
Figure 4b is the cross-section of Figure 4a at T1/2 = 60 min. The
Dncrit lines for Cmax and AUC show different trends. For Cmax
BE, as the permeability of a drug becomes higher, a faster dissolution is required (Table 3). This might be one of the reasons
for that some of the BCS class I drugs failed to show Cmax BE
even when they complied with the rapid dissolution criteria.77
Several low-permeability drugs show clinical BE even when
the dissolution profiles significantly differed among the formulations, for example, cimetidine,78 fexofenadine,79 and so on.
The Cmax of a high-permeability and short half-life drug can be
sensitive to the dissolution profile, for example, ibuprofen.80
In the Do > 1 cases, the Dncrit plane shifts lower, suggesting
that AUC and Cmax become less sensitive to the dissolution
DOI 10.1002/jps.24391

rate. Therefore, it is safe (conservative) to use Figure 4a for the

Do > 1 cases as well. Some of the transporter and paracellular
substrates are mainly absorbed from the upper small intestine.
In this case, Tabs can be shorter than 3.5 h, so that a larger kdiss
should be used as the dissolution rate criteria for AUC BE (cf.
kdiss = Dn/Tabs ).
A similar approach can be applied to take the gastric emptying rate into account. The dissolution rate should be approximately fourfold faster than the gastric-emptying rate for Cmax
BE of a short half-life drug. When using the gastric-emptying
half-life of 10 min, in vivo T85% should be shorter than 5 min
(Dncrit > 84).
Do Discriminate Point. The discriminate point next to Dn >
Dncrit is the Do discriminate point (Fig. 2). We can define the
critical dose number (Docrit ) as the highest Do value that provides a sink condition in vivo. Docrit < 1 is used in the BCS-BWS
guidelines. To ensure a sink condition, it might be safer to use
Docrit < 0.3 as the EIE condition. Thirty percent of the saturated solubility is often used as a criterion for a sink condition.
When Do > Docrit , Do1 = Do2 is required to prove the BE (together with Pn1 = Pn2 as the oral absorption becomes SL in
this case).
Pn Discriminate Point. The discriminate point next to Do <
Docrit is the Pn discriminate point (Fig. 2). We can define the
critical permeation number (Pncrit ) as the lowest Pn value that
provides the Cmax and AUC ratios of more than 0.8 against the
theoretically highest permeability case of Pn = 20. Pn = 20 is
calculated based on the highest permeability value observed in
humans (Peff = 10 104 cm/s for glucose) and adjusted for
the average molecular weight of modern drugs (400).81 Figure
5 shows the relationship between Pncrit and T1/2 . For drugs
with T1/2 > 600 min, Pncrit is approximately 2, whereas for
drugs with T1/2 less than approximately 600 min, Pncrit is larger
than 2. When Pn < Pncrit , Pn1 = Pn2 is required to prove the
BE.
Proofs for EIP and EIE Conditions
The strategies to prove the EIP and EIE conditions are summarized in Table 4 (conditions AG). The EIP and EIE conditions
discussed above are for in vivo, but not for in vitro. Therefore,
a justification is required when using in vitro data to prove in
vivo conditions, for example, IVIVC and a safe margin.
Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

REVIEW

Figure 4. The relationship among Dncrit , Pn, and T1/2 . (a) Dncrit plane satisfying both AUC BE and Cmax BE. (b) Cross-section at T1/2 =
60 min. The AUC and Cmax lines satisfy the equivalence of AUC and Cmax , respectively. The Dcrit values for Pn > 2 (Fa > 0.850.90) and
T1/2 < 10 h become higher than that for the Pn < 2 cases.
Table 3. Dissolution Criteria for Biowaiver
T85% (min)a

Dncrit
Pn

T1/2

AUC

Cmax

BEb

Dncrit 3c

FaCS Based

Current BCS-BWS

0.2
0.2
2
2
20
20

60
600
60
600
60
600

4.7
4.7
3.0
3.0
1.7
1.7

2.5
4.3
2.9
2.6
9.2
2.3

4.7
4.7
3.0
3.0
9.2
2.3

14
14
9.0
9.0
28
6.8

28
28
45
45
14
59

15d
15d
30
30
30
30

85% dissolution time.

Take the larger Dncrit .
SMF = 3 was used as an example.
d
EMA and WHO guidelines.
b
c

r The constituents of the intestinal fluid in vivo such as bile

A. Dn > Dncrit

micelles usually increase the solubility of a drug.

The conditions of a compendium in vitro dissolution test

could be dissimilar with those in vivo dissolution. Therefore,
an appropriate safe margin should be applied when using an
in vitro dissolution test as a surrogate for in vivo dissolution.
Usually, the dissolution rate criterion is described by the time
to reach 85% dissolution in an in vitro dissolution test (in vitro
T85% ). In vivo Dncrit can be converted to in vitro T85% as:
In vitro T85% =

Tabs ln (1 0.85)
Dnctir SMF

supersaturated solubility.
Therefore, the equilibrium solubility of an API in plain
buffers should be smaller than the apparent solubility of a drug
in vivo from a drug product. Consequently, in vivo Do < Docrit
can be proved by using in vitro data (in vivo Do < in vitro Do <
Docrit ).

(25)

where SMF is the safe margin factor. For AUC BE of a lowpermeability drug, Dncrit > 5 is required. When applying
SMF = 3, in vitro T85% becomes approximately 30 min (Table 3). For a high-permeability drug with T1/2 = 60 min, in vitro
T85% should be set 15 min for Cmax BE (Table 3).
B. Do < Docrit
The following three reasons would justify the use of the in
vitro equilibrium solubility of an API in plain buffers to prove
Do < Docrit of a drug product in vivo.
Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

r The excipients increase the solubility of a drug.

r The equilibrium solubility of a drug is smaller than the

C. Pn > Pncrit
In the T1/2 more than approximately 600 min range, Fa >
0.850.90 (Pn > 2) would be appropriate to justify biowaiver
(Fig. 5). However, in the T1/2 less than approximately 600 min
range, it does not guarantee Cmax BE. When Pn < Pncrit , a proof
for Pn1 = Pn2 in vivo is required [see sections (F) or (G) below].
When using a clinical Fa value for the permeability criterion,
no safety margin would be required. However, when an in vitro
permeability assay is used as a surrogate, an appropriate safe
margin would be required.
D. Dn1 = Dn2
DOI 10.1002/jps.24391

REVIEW

E. Do1 = Do2

10
9

Pn crit for 80% C max or AUC

The apparent solubility of a drug can be increased by the

excipients in the drug product. Therefore, the solubility of an
API cannot be used to prove Do1 = Do2 of drug products. A
dissolution test with a sink condition cannot be used to prove
Do1 = Do2 . A nonsink dissolution test with biorelevant media
may be used to prove Do1 = Do2 , especially for supersaturable
APIs and formulations.52

8
7
6

(b)

(a1)

5
F. PUWL1 = PUWL2

UWL line

4
3

(c2)

(a2)

2
1

(c1)

AUC = 80% line

(Fa= 0.8)

0
60

600
EliminationT1/2 (min)

6000

The permeability of a drug can be affected by the excipients

in the drug product. However, it is highly likely that most of the
excipients have little or no effect on PUWL (diffusion through a
water layer). It would be difficult to judge the rate-limiting step
in permeability from the in vivo Fa data, as Fa > 0.98 (Pn >
4) is required to be UWL limited. In an in vitro assay such as
Caco-2, the apparent permeability (Papp ) should be more than
50 106 cm/s to ensure UWL-limited permeation. Therefore,
a sufficient agitation is necessary for an in vitro assay.
G. Pep1 = Pep2

Figure 5. The relationship between Pncrit and T1/2 . When Pn is above

the Pncrit line [(a1) and (a2) areas], Pn satisfies EIE for both AUC
and Cmax . Fa > 0.850.90 data can be used in the T1/2 more than
approximately 600 min range. When Pn is below the Pncrit line, EIP
should be proved. PUWL1 = PUWL2 is required in the (b) area and Pep1 =
Pep2 is required in the (c1) and (c2) areas. Fa < 0.8 can be used to prove
that the permeability is limited by the epithelial membrane, whereas
the other approach is required to diagnose the rate-limiting step for the
Fa > 0.8 cases [the (b) and (c2) areas].

Summary for Biowaiver Strategy

An IVIVC strategy can be applied to prove Dn1 = Dn2 .82 In

IVIVC, in vitro dissolution profiles have to be proved to correlate with those in vivo. When Dn << Pn/Do, Fa becomes
sensitive only to Dn and insensitive to Do and Pn. As Pn and
Do become EIE in this case, the last piece to prove the Fa
congruent conditions is Dn1 = Dn2 (so that EIP of Dn). Usually, for a controlled-release formulation, high-solubility/ highpermeability drugs (Pn > 2 and Do < 1, therefore, Pn/Do > 2) is
selected to ensure a good absorption from the whole GI tract.83
By applying the 80% dominancy rule, Dn < 0.4 is sufficient for
Fa to be DRL. Dn = 0.4 corresponds to ca. 50% release at 5 h.

All in all, the discussion based on the Fa equation and FaCS

suggested that a drug product with a high permeability (Pn >
2), low solubility to dose ratio (Do < 0.3), and long elimination
T1/2 (>10 h) would be most suitable for biowaiver with the data
of in vitro T85% < 30 min, in vitro Do < 0.3 and Fa > 0.850.9
(Table 5). Therefore, the discussion based on FaCS basically
supports the biowaiver for BCS Class I drugs except for the
short elimination T1/2 cases. In the FaCS-based discussion, Pn
plays two distinct roles: (1) the determination of dissolution
criteria (with T1/2 ), and (2) the proof of Pn equivalence. The
FaCS-based discussion would provide some hints about what
should be carried out to improve biowaiver strategy and in vitro
tests in the future.85

In contract to PUWL , it is well known that Pep can be altered

by some excipients,84 especially for transporter and paracellular substrates. Once these excipients are excluded from the
formulation, Pep1 = Pep2 could be anticipated.

Table 4. Equivalent-in-Effect and EIP Conditions Suggested by FaCS

Conditions
Equivalent-in-effect (EIE)
(A)
Dn > Dncrit
(B)
Do < 0.3
(C)
Pn > Pncrit
Equivalence of independent parameter (EIP)
(D)
Dn1 = Dn2
(E)
Do1 = Do2
(F)
PUWL1 = PUWL1
(G)
Pep1 = Pep2

Measures

Criteria

In vitro dissolution test

In vitro solubility test
Clinical Fa data
In vitro permeability test

In vitro Dn > Dncrit SMFa

In vitro Do = Dose/(Sblank V) < 0.3
Fa > Fa (Pncrit )b
Pn (from in vitro Papp )c > Pncrit SMF

IVIVC
Not known
In vitro permeability
Excipient restriction

IVIVC criteria
Not known
PUWL d < VE fu Papp SMF
No excipient affecting Pep

SMF depends on the predictability of an in vitro test.

Fa = 0.85 and 0.90 corresponds to Pn = 1.9 and 2.3, respectively.
Pn calculated from Papp by Eqs. 4 and 14.
d
PUWL estimated from Deff (Ref. 36).
b
c

DOI 10.1002/jps.24391

Sugano and Terada, JOURNAL OF PHARMACEUTICAL SCIENCES

10

REVIEW

Table 5. Biowaiver Strategy

Type of Equivalencea
Dn
EIE (A)
EIE (A)
EIE (A)
EIE (A)
EIE (A)
EIP (D)

Do
EIE (B)
EIE (B)
EIE (B)
EIP (E)
EIP (E)
EIEg

Pn
EIE (C)
EIP (F)
EIP (G)
EIP (F)
EIP (G)
EIEg

FaCS

BCSb

Comments

+
PL-Ue
PL-Ef
SL-U
SL-E
DRL

I
I
III
II
IV
N/A

Most suitable for biowaiver

Likely to be PUWL1 = PUWL2
Excipient restriction for Pep1 = Pep2
Challenge to prove Do1 = Do2
Least suitable for biowaiver
IVIVC to prove Dn1 = Dn2

PL-Uc

PL-Ed

a
See test and Table 4 for the annotation of each alphabet. The color filling indicates the levels of challenge to prove the BE conditions; green, OK for biowaiver;
yellow, almost OK; orange, needs more scientific evidence; red, significant challenge required.
b
BCS classes approximately corresponding to each biowaiver strategy.
c
Area (a1) in Figure 5.
d
Area (a2) in Figure 5.
e
Area (b) in Figure 5.
f
Areas (c1) and (c2) in Figure 5.
g
Derived from Dn << Pn/Do.
N/A, not applicable.

CONCLUSION
The theoretical investigations discussed here can significantly
contribute to a better understanding of oral drug absorption.
They can provide guidance for API form selection, formulation
design, and biowaiver strategy. Although it is likely that computational simulations will be used more widely in the future,
analytical solutions and classification systems will continue to
provide a way to understand the fundamentals of oral drug
absorption.

ACKNOWLEDGMENTS
The authors greatly appreciate Prof. Gordon Amidon, Prof.
Shinji Yamashita, Dr. Ryusuke Takano, and Ms. Asami Ono
for their kind suggestions and discussions. The authors also
greatly appreciate the reviewers for their kind suggestions to
improve the manuscript.

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DOI 10.1002/jps.24391