Sugano 2009

Review
Introduction to computational
oral absorption simulation
Kiyohiko Sugano
Pﬁzer - Research Formulation, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
1. Introduction
2. Simulation: overview of COAS Computational oral absorption simulation (COAS) is anticipated to be
3. Concentration: states of drug
a powerful tool in improving the productivity of drug discovery and
molecules in GI tract development. This article reviews the theories of pharmaceutical sciences
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Universite De Sherbrooke on 12/05/12
that consist of COAS. Although most of these theories are classical, they
4. Solution: pH solubility profile in
are revisited from the context of modern drug discovery and development.
GI fluid and bile micelle media
The theories of solubility, diffusion, dissolution, precipitation, intestinal
5. Diffusion: effective diffusion
membrane permeation and gastrointestinal transit are comprehensively
coefficient in bile micelle media
described. Prediction strategy is then discussed based on the biopharmaceutical
6. Dissolution: Nernst-Brunner classification system. In the final part, good simulation practice is proposed
equation revisited and many frequently asked questions answered.
7. Precipitation: nucleation of
new solid form Keywords: dissolution, oral absorption, permeability, precipitation, simulation, solubility
8. Permeation: absorption into

Expert Opin. Drug Metab. Toxicol. (2009) 5(3):259-293
body
9. GI transition: mathematical 1. Introduction
expression of GI transition
For personal use only.
10. Extension: drug delivery The purpose of this review article is to provide a comprehensive introduction to
systems, food effects and computational oral absorption simulation (COAS). COAS is anticipated to be a
biological processes powerful tool to improve the productivity of drug discovery and development [1].
11. Integration: analytical and
Several COAS programs are commercially available and are being more com-
numerical solutions
monly used in drug discovery and development [2]. For a high-level understand-
ing of COAS, several excellent review articles are already available [3-5]. Therefore,
12. Application: prediction process
instead of repeating the high-level reviews in this article, every process of COAS
step and BCS based approaches
is discussed comprehensively, explicitly and in detail. At the same time, many
in drug research
references for further details are provided.
13. Conclusion In the first and main part of this article, focus is placed on the mathematical
14. Expert opinion equations that consist of COAS (Sections 2 – 11). In these equations, interaction
between gastrointestinal (GI) physiology and drug property is explicitly expressed.
Although most of the theories used in COAS are classical, these should be
revisited from the context of modern drug discovery. Therefore, low solubility
and low permeability drugs are examined in this article [6-8].
In the second part of this article (Section 12), the strategy of COAS is discussed.
The key simulation attributes that differ depending on the solubility and permeability
are discussed according to the biopharmaceutical classification system (BCS) [9].
In the last part of this article, a proposal for good simulation practice is
discussed along with some frequently asked questions for COAS (Section 14).
The accuracy of drug parameters is critically important for appropriate simulation.
Many excellent review articles for solubility [6,10-13] and permeability [13-16] mea-
surements are available. Therefore, detailed explanation for in vitro and in vivo
experiments is not repeated in this article. However, the connection of COAS
with these experiments is suggested at pivotal points. It should be stressed that
COAS should be aligned with the strategy of in vitro and in vivo assays in drug
discovery and development.
The accuracy of physiological parameters is also critically important for COAS.
Excellent review articles of physiological parameters are also available with com-
prehensive summary tables [17-24]. Therefore, detailed explanation for physiological
10.1517/17425250902835506 © 2009 Informa UK Ltd ISSN 1742-5255 259

All rights reserved: reproduction in whole or in part not permitted
Introduction to computational oral absorption simulation
Transit
Transit
Transit
Nernst Brunner equation Permeation equation
(Section 6) (Section 8)
Dissolution Dissolved drug Permeation Absorbed drug

Capsule/Tablet Disintegration API particles (Xdissolv)
(XAPI) (Xabs)
Precipitation
n
tio
Classical nucleation ta n
Transit models
p i tio
theory (Section 7) eci
(Section 9)
lu
Intestinal membrane
o
Transit
r
Transit
P iss
Transit
-d
Re
New solid form
(XNFP)
Transit
Figure 1. Schematic presentation of oral absorption from a dosage.

parameters is not repeated in this article. However, the absorption of a drug and focus on the rate limiting step. A
knowledge of GI physiology has been dramatically increased comprehensive illustration of these categories is available
in recent years. Therefore, several recent updates relevant to elsewhere [6].
COAS are discussed at the end of each section.
2.2 Why mathematical equations?
2. Simulation: overview of COAS
“… it (mathematics) is the spine that renders scientific speculation
sufficiently rigid to confront experience. Scientific hypothesis
2.1 Conceptual explanation of oral absorption
themselves are like jelly; they need the rigidity of mathematical
The process of oral absorption from a drug product is shown formulation if they are to stand up to experimental verification
in Figure 1. After dosing a drug product, the formulation and fit into the network of concepts that constitute physical
disintegrates to release drug particles. The drug particles science [26].”
(active pharmaceutical ingredient, API) dissolve into the GI fluid. Peter Atkins
The formulation, drug particles and dissolved drug transit
through the GI tract. The dissolved drug permeates the COAS is the integration of many theories of pharmaceutical
intestinal wall and reaches the blood flow. Basically, these sciences that are expressed as mathematical equations. An
processes occur for all oral drugs. However, the rate limiting example flowchart of COAS is shown in Figure 2. This
process is different for each drug and can be categorised as [25]: flowchart is based on the theoretical equations readily avail-
able in the literature and has been implemented as a com-
• Permeability limited absorption: After oral administration,
puter program by our group. (Therefore, this flowchart is
the drug dissolves immediately. However, permeation is
not exactly the same as that of the commercial programs.
slow. The dissolved amount accumulates in the GI fluid,
However, the basic concepts of COAS are considered as
but does not reach saturated solubility.
being covered.) In the following sections, each equation of
• Dissolution limited absorption: Dissolution is much slower
the flowchart is explained step-by-step. It is important to
than permeation. The dissolved drug instantly permeates
clearly recognise that an equation describes how the drug
the intestinal membrane. The dissolved amount in the GI
property and physiological property interact in the mode of
fluid remains below saturation.
a mathematical operation. Each equation consists of:
• Solubility limited absorption: If dissolution is faster than
permeability, the drug may accumulate in the intestinal
• drug parameters: intrinsic solubility, dissociation constant,
fluid reaching saturated solubility.
diffusion coefficient, etc.
The rate limiting step mainly determines the oral absorption. • physiological parameters: pH, bile micelle concentration,
Therefore, it is important to form a clear view of the oral morphology of GI tract, transit time, etc.
260 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

Parameters Equations
Constant Standard rp,t=0 Dose(XAPIp,t=0) Chemical formula
Changes with time Differential equation
Initial value
Eq. 29 Eq. 33
Constant, depends on GI position
Solved by integration NAPI PSF (API) r (API)
Changes with time and GI position
Chemical structure/physicochemical property rp,API Eq. 30 Integration

End feed parameter for integration
Eq. 22 Eq. 31
Crystal
energy Eq. 7 S0
SA GI transit
h APIp
Eq. 5,6 Sbulk pUWL(API) X models
API
K sp Eq. 68,69
Lipophilicity Dissolution/particle growth

Eq. 8 K bm Eq. 5,6,19 Ssurface X Eq. 45 X
(Koct) Eq. 18 dissolv perm
hpUWL()NFP SANFP XNFP

Dissociation
constant Ka
(Ka) Absorption
Nucleation Eq. 22 Eq. 31
Eq. 44 γ Eq. 48
Eq. 43
Fh
Eq. 34 vm
r Eq. 30 PK models
Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

p,NFP
NNFP
PSF (NFP) r (NFP)

Size Eq. 14 Dmono Eq. 11 Deff
Eq. 33
Chemical formula
Eq. 63 P
para
Eq. 67 P Eq. 59 P Eq. 55 PUWL

trans,0 trans
Eq. 52,53 P Eq. 48 k
P eff abs
Eq. 66 active Eq. 56 Pep
Figure 2. Overview flowchart of computational oral absorption simulation.
261
Sugano
• mathematical operations: +, -, ×, exponential, logarithm, The effective concentration for a reaction, such as dissolution
differential, integral, if–then, etc. and permeation, depends on the ‘availability’ of the state for
the reaction (Figure 3).
As shown in Figure 2, the calculation process is connected
throughout from the chemical structure of a drug to the 4.Solution: pH solubility profile in GI fluid
oral absorption in humans. Therefore, technically, it is pos- and bile micelle media
sible to predict the oral absorption from the chemical struc-
ture. However, usually the prediction error would be The solubility of a drug in the GI fluid is one of the
enormous by this method due to prediction error multiplies most important parameters for COAS. The solubility value
of each individual process. Therefore, in vitro and in vivo is used to calculate the dissolution rate of a drug particle
data should be used simultaneously when they are available. (Section 6) and the precipitation rate (Section 7). In addition,
The sequence of mathematical equations, which is the entity in many cases, the solubility value determines the maximum
of COAS, offers a scaffold to integrate in silico, in vitro and concentration available for permeation (Section 8).
in vivo data [27] (in this article, ‘in silico’ means calculation It is well known that the solubility of a drug depends on the
from chemical structure). pH of the fluid. In addition, in the case of low solubility
The end-feed parameters for integration (indicated as compounds, bile micelles play an important role in oral
solid white letters in Figure 2), such as the absorption rate absorption. Therefore, the effects of pH and bile micelles should
constant (kabs), are commonly used in most commercial and be appropriately considered in the theoretical equations.
in-house programs. The accuracy of these end-feed parame-
ters predominantly determine simulation accuracy, whereas 4.1 Definition of solubility
the integration method has little effect. In this article, the The definition of solubility was extensively discussed
theoretical estimation methods of end-feed parameters are previously [6]. In this article, solubility refers to the equilibrium
discussed in detail. Usually, the end-feed parameters prepared solubility, not the kinetic solubility or supersaturation
by the user can be used for integration in addition to those concentration. The solubility and dissolved amount (Sdissolv
calculated by the default method provided by the program.
and Xdissolv) are defined as the sum of free monomer and bile
micelle bound molecule (Xmono and Xbm, respectively):
3. Concentration: states of drug molecules in
GI tract (3)
X dissolv = X mono + X bm
When we perform COAS, it is important to be conscious
of which molecular states are involved in the process
(4)
of interest. Drug molecules can exist in various molecular
states in the GI tract, and the molecular states involved for X dissolv
C dissolv =
dissolution and permeation processes are different (Figure 3). VGI
In this article, undissociated monomer molecule, dissociated where Cdissolv is the effective concentration for dissolution
monomer molecule, bile micelle bound molecule, formula- and VGI is the volume of GI fluid.
tion bound molecule and solid particle are considered. It would be easier to understand the reason for this definition
The total amount and concentration of a drug (Xtot and by thinking of API as consisting of two particle sizes, for
Ctot, respectively) in a GI fluid is expressed as the sum of example, 200 nm and 20 µm. Because the solubility value is
each species as: used to simulate the dissolution process in COAS (Section 6), the
(1) molecular states involved in the dissolution process, which are,
X tot = X mono ,z + X bm + X fm + X API + X NFP monomer and bile micelle bound molecules, should be taken
into account. As shown in Figure 3, a solid drug dissolves as
monomer and bile micelle bound molecules, but not as nano
(2)
particles. Therefore, it would be appropriate to define ‘solubility’
X tot
C tot = as the sum of free monomer and bile micelle bound molecules.
VGI
On the other hand, nano solid particles might be able to perme-
where X is the amount of drug, C is the concentration, ate the mucus layer (Sections 8.4 and 10.1). Therefore, nano
subscript mono, z (expressed as 0,+,-,++,--,… in the following solid particles are considered to be effective for permeation.
sections), bm, fm, API and NFP indicate monomer molecule
(z:charge), bile micelle bound molecule, formulation bound 4.2 pH solubility profile in bile micelle media
molecule, API particle and newly formed precipitant Solubility values in artificial biorelevant media, such as fasted
particle, respectively. It should be noted that the total and fed state simulated intestinal fluid (FaSSIF (taurocholic
concentration of a drug by this definition contains large acid; TC: 3 mM, phosphatidylcholine; PC: 0.75 mM,
solid particles. pH 6.5 ), and FeSSIF (TC: 15 mM, PC: 3.75 mM,

Sugano
Particle velocity
Conc.
Free monomer molecule
Bulk flow
C
gr onc Micelle bound molecule
Relative velocity
ad e
ie ntr
nt at
io Nano particles of API
n
Distance
Di
ffu
sio
n
Dif
fus
ion
Unstirred water layer

on particle surface Kbm
Diffusion
Diffusion
Conc.
Convection
Convection
Co
ce n
n
Unstirred water layer
tra
on intestinal membrane
tio
gran
d
Distance
ien
t
Epithelial cells at villi top
Figure 3. Dissolution and intestinal membrane permeation of a drug. The upper part illustrate the dissolution process. The
lower part illustrate the permeation process.
pH 5.0 – 6.5), respectively) [28,29], which mimic the In these equations, intrinsic solubility (the equilibrium
human intestinal fluid, have been used for oral absorption solubility of an undissociated species in aqueous media
simulation [30,31]. However, it may be impractical to experi- without bile micelles, S0), dissociation constant (Ka) and bile
mentally measure all solubility values representing various micelle water partition coefficient for undissociated (Kbm,0)
GI positions, animal species and individuals in drug discovery. and charged species (Kbm,+ and Kbm,- for mono cation and
Therefore, it is important to use an appropriate equation mono anion, respectively) are drug parameters. pH ([H+])
that enables estimation of solubility values representing various and bile micelle concentration (Cbile, expressed as bile acid
GI conditions from a few intrinsic parameters. The modified concentration) in each GI position are the physiological
Henderson–Hasselbalch (HH) equation (Equations 5 and parameters. Cwater is the concentration of water (55.5 M).
6) [32-34] can be used to calculate a solubility value in a The standard HH equation (which does not consider the
GI fluid at a given GI position (Sdissolv) [35,36]. Typical pH bile micelle partition) should not be used for bile micelle
solubility profile of a basic compound is shown in Figure 4. media (Figure 4). In the pH region in which the common
ionic effect limits the solubility, a equation that considers
(5) the solubility product (Ksp) and the counter ion concentration
has to be used (Equations 2 – 6 in ref. [6]).
 H +  C H +  C 
S dissolv = S 0 1 +   + bile ⋅ K bm ,0 +   ⋅ bile ⋅ K bm ,+  for a base The bile micelle concentration and pH of the GI fluid
 Ka C water K a C water  have a significant effect on the solubility of a drug in the GI
fluid, and, therefore, are briefly introduced here. Bile acid
(6) concentration has a large variation among animal species
 
and the fasted/fed states: ∼ 2 – 5 mM (humans, fasted) [37],
C C
S
K
= S0 1 + a + bile ⋅ K
K
+ a ⋅ bile ⋅ K  for anacid 15 mM (humans, fed) [37], ∼ 10 – 20 mM (rats) [38], 5 mM
dissolv  H +  C water bm ,0 H +  C water bm ,− 
      (dogs, fasted) and ∼ 13 – 18 mM (dog, fed) [39,40]. Stomach
Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 263

Standard HH equation relationship between the physicochemical properties and the

Standard HH equation using solubility in solubility in biorelevant media (Equations 7 [44-46] and 8 [35]):
bile micelle media as S0
Modified Henderson-Hasselbalch equation (7)
100 Experimental data without bile micelles
log S 0 (mol / L ) = 0.5 − 0.01 ⋅ (mp − 25) − log K oct,0
Experimental data with bile micelles
10 (8)
log K bm ,0 = 0.74 log K oct,0 + 2.29
Solubility (mg/ml)
1 where Koct,0 is the octanol water partition coefficient

(partition coefficient of undissociated species). Both solubility
and bile micelle partition are related to lipophilicity expressed

0.1 as log Koct,0. In addition to lipophilicity, the melting point
(mp) is another key parameter for solubility and should be
considered in drug design [47-51]. The bile micelle partition
0.01 coefficients of mono cation and anion (Kbm,+ and Kbm,-,
respectively) can be estimated as Equations 9 and 10 [36,52]:
(9)
0.001
3 4 5 6 7 8 log K bm, + ≈ log K bm,0 −1
pH
(10)
Figure 4. Typical pH solubility profile of a basic compound log K bm,−≈log K bm,0 − 2.
(dipyridamole) [35].
Both positively and negatively charged drug molecules

can bind to bile micelles, the lipophilic part of the drug
pH also has a large variation: pH ∼ 1.5 (human, fasted) [37], molecules being embedded in the lipophilic core of micelles
pH 6 (human, fed) [37] and pH ∼ 3 – 5 (rats) [24]. and the charged moiety being exposed to the water. The
Stomach pH of dogs has large individual variation of pH surface of bile micelles are negatively charged by
∼ 1.5 – 5 [41,42]. The small intestinal pH is ∼ 5.5 – 7.4 [18]. the sulfonate (-S(=O)2-O−) and carbonate (-C(=O)O−)
functional groups of bile acids. Therefore, in addition to
4.3 Acquisition of solubility parameters in drug the lipophilicity of a drug molecule, the charge state of the
discovery and development drug molecule also affects the bile micelle binding of the
The experimental methods of solubility measurements are drug molecule.
reviewed elsewhere [6,10]. Solubility is typically measured by
the following procedures [6,10]: i) suspending a solid drug
5. Diffusion: Deff in bile micelle media
in a liquid media for enough time to reach equilibrium;
The diffusion coefficient affects the dissolution rate (Section 6),
ii) removing the residual solid material by filtration
precipitation (Section 7) and intestinal membrane perme-
(typically 0.2 – 0.45 µm pore radius); and iii) measuring the
ation (Section 8). Therefore, the diffusion coefficient is
drug amount in the filtrate (e.g., by HPLC). The filtrate can
discussed beforehand.
contain drug particles existing at a smaller size than the
The effective diffusion coefficient (Deff) is determined by
filter pore size. Therefore, the particle size of a solid drug
the diffusion coefficient and the fraction of monomer and
should be larger than the filter pore size; otherwise, the
bile micelle bound molecules [53-58]:
filtrate can contain solid particles (especially nano particles)
and the solubility (as defined in this article, free monomer (11)
and bile micelle bound molecules) can be overestimated. D eff = D mono ⋅ f mono + Dbm ⋅ f bm
For low solubility compounds, bile micelle solubilisation
plays a key role in oral absorption. Therefore, a solubility value (12)
in a biorelevant media such as FaSSIF and FeSSIF should be
f mono + f bm = 1
used for simulation. Kbm values can be back calculated from
the measured solubility values in a biorelevant media and a
blank buffer without bile micelles. (13)
The in silico prediction of intrinsic solubility is still very
S dissolv (without bile micelles )
challenging in real drug discovery [43]. The following two f mono =
equations would be useful for understanding the general S dissolv (with bile micelles )

Sugano
where Dmono and Dbm are the diffusion coefficients of version of the Noyes–Whitney equation [65] and most often
monomer and bile micelle bound molecule, respectively, and used for COAS [66]. Firstly, the NBE is introduced, and
fmono and fbm are the fraction of monomer and bile micelle then, each parameter in the NBE is discussed.
bound molecule, respectively. In the case of lipophilic drugs
(log Koct,0 > 2), the drug molecules tend to bind to bile 6.1 NBE for oral absorption
micelles (Equations 5, 6 and 8), resulting in a smaller Deff The dissolution of a drug is a kinetic process. Therefore, the
than that of the monomer molecule. dissolution rate is described by a time-dependent differential
Several equations were reported to calculate Dmono in equation (d/dt). Two steps are involved in dissolution from the
aqueous media [59]. However, these equations are for 25˚C. solid surface (Figure 3). The first step is the detachment of a
Therefore, it is appropriate to correct the difference of molecule from the solid surface. The second step is the
viscosity between 25 and 37˚C (× 1.41): diffusion of the detached molecule across the diffusion layer
adjacent to the solid surface. In most cases, rapid equilib-

(14) rium (i.e., saturation) is achieved at the solid surface.
Therefore, the second step mainly determines the dissolution
( )
D mono cm 2 / sec = 10−4.113 − 0.4609× log MW × 1.41.
rate. The dissolution rate of drug particles can be expressed
For example, MW = 350, Dmono = 7.3 × 10-6 cm2/sec. by the NBE as [6]:
The diffusion coefficient of bile micelles can be
∼ 8 – 80 times smaller than that of a monomer molecule (18)
depending on the bile micelle size. The bile micelle size
dX API ,ij
depends on bile acid concentration [6,60,61]. In the case of = (Surface area )×(Diffusion through UWL)
TC:PC = 4:1 system, the bile micelle diameter (dbm) and dt
×(Correction for surface solubility )×(Concentration gradient)
Dbm (of blank micelle) can be predicted as [6]:
Deff Ssurface
= −SAAPI ,ij × × × (Sdissolv −C dissolv )
(15) h pUWLij Sdissolv
700 where XAPI,ij is the amount of drug (weight or mol) in a

d bm (nm ) = ⋅⋅⋅ C bile ≤ 3.98 mM
−7.90 × C bile (mM ) + 37.1 particle size bin i and a virtual particle bin j within each
particle size bin (each particle bin is referred as ij, Section 6.4).
(16) The particle bins are introduced to represent the particle size
distribution and the transfer of particles through the GI
1 tract (Section 9). SAAPI,ij is the total solid surface area of a
d bm (nm ) = + 5.31⋅ ⋅ ⋅ C bile > 3.98 mM
0.143 × C bile (mM ) − 0.562 particle bin (determined by particle radius (rp,ij) and density
(r); Section 6.4), hpUWL,ij is the effective diffusion resistance
(17) around the particle (effective thickness of the unstirred water
layer on the particle surface; pUWL). Ssurface is the solubility
( )
Dbm cm 2 /sec =
6.63
d bm (nm )
×10 -6 . at the solid surface introduced previously [6]. dXAPI,ij is added
to the dissolved amount in a GI position, k (Xdissolv,k) when
For example, for FaSSIF (Cbile: 3mM), dbm = 52 nm and the particle passes through this position (Section 9.3).
Dbm = 0.13 × 10-6 cm2/sec. It would be worth noting that In the following Section 6.2 – 6.5, the meaning of the
Dbm could be different for each GI position or each animal parameters in the NBE (i.e., Ssurface, hpUWL,ij, SAAPI,ij and r)
species, depending on the concentration and the composition are discussed (Sdissolv and Deff are already discussed in
of bile micelles (Section 4.2). Sections 4 and 5, respectively).
Okazaki et al. investigated the effect of drug inclusion
on the diffusion coefficient of bile micelles [62]. Undissociable 6.2 Solubility at solid surface
and acidic compounds were found to have little effect The solid surface solubility determines the dissolution rate
on Dbm. However, in the case of some basic compounds in the sink condition (Cdissolv ≈ 0). Ssurface/Sdissolv term in
(pKa > 6.5), drug inclusion had a large effect on Dbm, Equation 18 was introduced to appropriately simulate the
suggesting that Dbm should be experimentally measured. dissolution of dissociable compounds in a sink condition
Dbm can be easily measured by dynamic laser scattering. (i.e., corresponding to dissolution-limited absorption) [6], as
the solid surface solubility of a dissociable compound differs
6. Dissolution: NBE revisited from the equilibrium solubility in the bulk media.
In this section, the Nernst–Brunner equation (NBE), which 6.2.1 Dissolution of free acid/base
represents the dissolution rate of drug particles in the GI In the case of free acids or bases, pH at the solid surface
tract, is discussed in detail [63,64]. The NBE is an improved (pHss) no longer equals bulk pH owing to the self-buffering

effect of the dissolving drug at the solid surface. pHss is layer of less soluble free form on the surface [78]. Recently,
affected by both the dissolving drug molecules from the co-crystals have been actively investigated [79]. Dissolution
solid surface and the buffer molecules from the bulk from a co-crystal form would require similar considerations
medium. Various approaches for pHss calculation have been as that of salts [80].
reported [11,67-73]. pHss depends on S0, pKa of the drug, Deff,
pKa of buffer species (pKa,buffer), concentration of buffer 6.3 Unstirred water layer thickness of a particle
species (Cbuffer), diffusion coefficient of buffer species (Dbuffer) 6.3.1 Hintz Johnson and Wang Flanagan models
and bulk fluid pH (pHbulk): hpUWL,ij is a distance that represents the effective diffusion
resistance (based on the film theory, the film = pUWL) (Figure 3).
(19) hpUWL,ij can be estimated by empirical equations such as
pH ss = f (S 0 , K a , D eff , pK a,buffer ,C buffer , Dbuffer , pH bulk ). Hintz–Johnson [81] and Wang–Flanagan models (HJ and
WF models, respectively) [82,83] for spherical particles.

Once the solid surface pH is obtained, Ssurface can be
calculated by the HH equation. In the case of free acids and HJ model
bases, Ssurface is lower than the solubility in the bulk fluid
(Ssurface < Sdissolv). Therefore, if Ssurface/Sdissolv term is not used (20)
in Equation 18, the dissolution rate of free acids and bases h pUWL ,ij = rp ,ij rp .ij < hHJ
would be overestimated.
h pUWL ,ij = hHJ rp ,ij > hHJ
6.2.2 Dissolution of salts
Oral absorption of a salt form is usually higher than that of WF model
a free form, as salt formation increases the dissolution rate
and the effective concentration for permeation. Ssurface of a (21)
salt form is higher than that of a free form (basically, Ssurface
1 1 1
is determined by Ksp [74]), resulting in faster dissolution. In = +

h pUWL ,ij rp ,ij hWF
addition, after dissolution of a salt form, the concentration
in the GI fluid can reach a critical supersaturation concen- where rp,ij is the particle radius of the particle bin, ij. hHJ
tration above which the nucleation of a free form is initiated and hWF are the parameters that can be empirically
in several hours (Figure 5B and Figure 6 solid line) (Section 7). determined for a certain agitation condition. Usually, hHJ
The critical supersaturation concentration is usually and hWF are 20 – 30 µm assuming a standard agitation
much higher than the solubility of a free form. Once nucle- strength and average particle density. However, hpUWL,ij
ation is initiated, the particle growth of the nuclei precipi- changes depending on the particle density, agitation
tant of a free form leads to a decrease in the concentration. strength, fluid viscosity, fluid density and particle shape.
In COAS, this typical dissolution profile of a salt form can This can be appropriately represented by the fluid
be represented with a dissolution equation for a salt form dynamic model.
and further introduction of the equations for nucleation and
precipitant particle growth of a free form as: 6.3.2 Fluid dynamic model
The fluid dynamic model enables theoretical estimation of
• Dissolution of a salt form: represented by Equation 18 for
hpUWL,ij. In fluid dynamics, hpUWL,ij is calculated from the
a salt form (Sdissolv in the concentration gradient and
representative length (lp,ij) of a particle (for sphere, lp,ij = 2rp,ij)
Ssurface/Sdissolv terms are set equal to Ssurface, i.e., Ssurface - Cdissolv,
and the Sherwood number (Shp,ij) as:
and Ssurface/Sdissolv = 1, respectively) [75-77].
• Nucleation of a free form: represented by the classical (22)
nucleation theory (CNT) (Section 7).
• Particle growth of the nuclei precipitant of a free form: 1 Sh p,ij
=
represented by Equation 18 for a free form (with negative h pUWL,ij l p,ij
concentration gradient) (Section 6.2.1).
Shp,ij depends on the object shape, the object size,
In the case of a chloride salt, the dissolution rate in the kinematic viscosity of the fluid (n), fluid velocity relative to
stomach is determined by the solubility product and the the object (Vrel,ij) and Deff. Shp,ij can be calculated from the
concentration of chloride ion. In the case of other salts, after Reynolds number of the particle (Rep,ij) and Schmitt
the dissolution of the initial salt, chloride salt may precipi- number (Sc) as [84]:
tate out in the stomach, depending on the Ksp of these salts
and super-saturation extent in the stomach [74]. (23)
Precipitation of free form can occur at the solid surface of
salts. In this case, the dissolution of salt is hindered by the Sh p ,ij = A RM + BRM Re p ,ij C RM Sc DRM

A. Dosed as free base
N Dissolve in H+
N N
H+
Precipitate out
(as the same solid form of a dose (= free base)
B. Dosed as salts
Precipitate out
+ - + (as free form) N
Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

H Cl H
N Dissolve in N N
H+
(re-) Dissolve in
Figure 5. Precipitation of a basic compound. Identical form precipitation (A) and different form precipitation (B).
267
Sugano
Ssurface
Nucleation initiated
Nucleation terminated
Critical supersaturation
concentration
Prec
Concentration
form
ipitat
Without precipitation
n of a salt
ion
With precipitation
of a f
ree f
Dissolutio
rm o
Sdissolv
(equilibrium solubility of
Time a free form in the bulk)
Figure 6. Dissolution of a salt and precipitation of a free form in a buffered medium.
(24) (26)
l p ,ij ⋅V rel ,ij V rel ,ij = Vt ,ij 2 + V me ,ij 2
Re p,ij =
v
(27)
(25)
(
Vt ,ij = f ρ, rp ,ij , v )
v
Sc =
D eff (28)
Equation 23 is called the Rantz–Marshall equation [84].
The constants ARM to DRM depend on the object shape. For
(
V me ,ij = f rp ,ij , e )
a spherical object, ARM = 2, BRM = 0.6, CRM = 1/2 and Recently, a convenient calculation method of Vt,ij and
DRM = 1/3. Vme,ij was reported [88].
The first term of Equation 23 (ARM = 2) for spherical In some cases, the particles may sediment on the bottom
particle is derived as follows. Even without any flow, a particle of a vessel or the intestinal wall, depending on the particle
fixed in the fluid space dissolves into the fluid, because as size, density, agitation strength and fluid viscosity. When the
the distance away from the particle increases, the spherical particles sediment, Vrel,ij in Equation 23, becomes smaller,
surface area expands to produce a concentration gradient consequently, the dissolution rate becomes slower. In a
around the particle. This effect is called ‘asymptotic molecular stirred vessel, the maximum suspendable radius can be
diffusion’ or ‘the curvature effect’. (Without any flow around calculated by an empirical equation [89], or it may be
a particle, Vrel,ij = 0 and Rep,ij = 0. Therefore, Shp,ij of a approximated as the radius range where Vt,ij < vertical velocity
spherical particle is 2 and hpUWL,ij is rp,ij (hpUWL,ij = lp,ij / of the fluid in a system.
Shp,ij = 2rp,ij/ Shp,ij). However, it should be noted that, without For further sophisticated simulation of fluid dynamics,
any flow, the real thickness of pUWL is infinite. hpUWL,ij is computational fluid dynamics methodology that numerically
not the real thickness of pUWL, but the effective thickness integrates the Navier–Stokes equation would be required [90-93].
of pUWL represented as length-1 dimension).
The second term of Equation 23 represents the effect 6.4 Solid surface area
of flow around a spherical particle. When the particle is As the particles dissolve, the surface area of the particles
suspended in the fluid, the particles flow with the fluid. reduces. To represent this process, the number of particles in
Therefore, Vrel,ij is the relative velocity between the fluid and a particle bin (NAPI,ij) is firstly calculated. NAPI,ij remains con-
the particle velocities (Figure 3). TheVrel,ij mainly consists of stant during the oral absorption process. From NAPI,ij and the
the terminal (sedimentation) slip velocity (Vt,ij) and remaining undissolved amount of the particle bin at time
microeddy effect (Vme,ij) [83-87]. Vt,ij reflects the true density t (XAPI,ij), the particle radius and the surface area of the particle
of a drug (r) and Vme,ij reflects the agitation strength (e): bin at time t (rp,ij and SAAPI,ij, respectively) can be calculated.

Sugano
When spherical shape is assumed, the number of particles (34)

in the ijth particle bin (NAPI,ij) can be calculated as [81,94]:
( )
v m cm 3 / mol = 3.85 ∑ m atom ⋅ v atom
(29) atom
where vm is the molecular volume, matom is the number of

N API ,ij =
(Initial weight of a particle bin ) = f bib ,ij ⋅ Dose
atoms in the molecule and vatom is the relative volume of the
(Initial weight of a particle ) 4
p ⋅ rp ,ij ,t = 03 ⋅ r atom that is 1 for H, 2 for the first short period in the periodic
3 table (Li-F), 4 for Na-Cl, 5 for K-Br and 7.5 for Rb-I.
where fbin,ij is the fraction of a dose (Dose (= Âij XAPI,ij,t=0 )) in a
particle bin ij and rp,ij, =0 is the initial particle radius (t = 0). 6.6 Physiological parameters: agitation strength and
t
As a particle dissolves, XAPI,ij and rp,ij decrease whereas buffer concentration
NAPIij remains constant (complete dissolution of a particle is Deff, Sdissolv, Ssurface, and hpUWL,ij values can be different at
represented by setting XAPI,ij to 0) [94]. The particle radius at each GI position and in each in vivo species, as pH, bile
time t can be calculated as: concentration, buffer concentration and agitation strength
can be different. (Physiological pH and bile concentration
(30) are already discussed in Section 4.3.)
1/3 The agitation strength is different between dogs and
 X API ,ij 1 3 
rp ,ij =  ⋅ ⋅ 
 N API ,ij r 4p 
(derived from X API ,ij =N API ,ij = N APIij × 4 / 3P rp,ij 3 × r ) humans [40,100,101]. It is difficult to directly estimate e value
for in vivo GI tract. It was reported that the agitation
Surface area of particle group ij is then: strength in the human GI tract corresponds to ∼ 20 – 75 rpm
in the USP paddle method [40,100]. The e value of this pad-
(31) dle speed is ∼ 0.0003 – 0.014 m2/s3 [88,102].
The buffer concentration in the GI fluid (HCO3-,
SA API ,ij = N API ij ⋅ 4p rp ,ij 2 ⋅ PSF .
6.7 mM) [37] is lower than that of the buffers usually used
Particle shape factor (PSF) was introduced to represent for dissolution testing [103]. Therefore, the dissolution rate of
the deviation of surface area from the spherical particle. When dissociable compounds could be overestimated by a standard
spherical approximation is not adequate, particle shape dissolution test condition.
should be taken into account. Simple surface area correction
would give a first approximation for shape effect [95]: 6.7 Acquisition of drug parameters
The mini scale dissolution test [30,31], µDISS and µIDR [73],
(32) would be suitable for drug discovery. Solid surface solubility
Surface area of a particle can be determined by suspending an excess amount of API
PSF = . in an unbuffered medium of a pH [76,77,104].
Surface area of a volume equivalent sphere
For example, for a cuboid of 1:1:5 ratio, PSF = 1.56. 7. Precipitation: nucleation of new solid form
However, the hpUWL,ij (and Shp,ij) on a particle surface is not
homogeneous (Figure 3) [96,97]. Therefore, hpUWL,ij should The solubility of a basic compound is higher at lower pH.
also be appropriately corrected. However, a simple equation Therefore, the drug dissolved in the stomach could precipitate
to estimate the effect of particle shape on hpUWL,ij is not out in the small intestine. Salts of acidic compounds can
known at present. also precipitate out as free form, especially in the stomach.
It would be preferable to use the measured particle size Precipitation in the GI tract can be categorised into two
distribution. However, a log-normal distribution is often types: free base API case (Figure 5A) and salt form API case
assumed as a typical distribution pattern. (Figure 5B). In the case of free base API, it would be
appropriate to assume that a portion of administered drug
6.5 Density particles can reach the small intestine before completely dis-
The true density of drugs is 1.1 – 1.5 g/cm3 range in most solving in the stomach. Therefore, these particles can be the
cases [98]. The experimental true density data are not always nuclei for precipitation. The reduction of Cdissolv occurs by
available at the drug discovery stage. Therefore 1.2 g/cm3 is the particle growth process, which can be represented by the
often used as the average value. Girolami developed a simple NBE with a negative concentration gradient [94] (Section
‘back of the envelope’ method to calculate true density from 6.3.2; however, nucleation may also occur depending
a chemical formula [99]: on Cdissolv in the small intestine). On the other hand, in
the case of salt form API, a nucleation process for free form
(33) (= precipitant solid form) is additionally required for
( )
r g / cm 3 =
MW
vm
precipitation to occur (Section 6.3.2). Therefore, in this
section, focus is placed on the nucleation process.

At present, there are many unknown factors for nucleation. (39)

However, CNT has been used to simulate precipitation [105].
Although the applicability of CNT for COAS would be Fnc = (Surface area ) × (collision rate per area )
the subject of further investigation, CNT is briefly intro- × (Concentration )
duced in this section for understanding the fundamental jnc Dmono
= 4prp ,nc 2 ⋅ × N AC 0
mechanism of nucleation. The theory described in this rp ,nc
section does not consider other factors such as secondary
nucleation and aggregation.
(40)
7.1 Classical nucleation theory 2 ⋅g ⋅vm
rp ,nc =
The number of molecular clusters, which could be the nuclei for k BT ⋅ ln (C 0 / S 0 )
precipitation, depends on the free energy barrier for formation

of cluster (Figure 7). When the cluster size is smaller than the (41)
critical size, the increase of interfacial energy (∞r2) is larger than
h pUWL
the decrease of volume energy (∞r3). Therefore, in this case, the j nc =
nuclei cannot grow further. Once the critical size is achieved, lnc + h pUWL
the precipitation process is controlled by the growth process. where lnc represents the contribution of interfacial
According to the CNT, the primary nucleation rate per attachment rate as the length dimension. By combining
volume per time (Jnc) can be expressed as [106]: Equations 35 – 41 [106] we arrive at:
(35) (42)
dN nc
= (number of critical cluster )
1/ 2
J nc = 2 k T 
dt J nc = j prec , k ⋅ D mono ⋅ (N A ⋅ C 0 ) ⋅  B 
× ( frequency of addition of another molecule)  g 
 16p  g   3
 
2
= C nc × Fnc vm
ln (C 0 / S 0 ) ⋅ exp  -     
 3  k BT   ln (C 0 / S 0 )  
where Nnc is the number of nuclei, Cnc is the number  
of critical cluster per volume and Fnc is the frequency of where C0/S0 is the degree of supersaturation. The nucleation rate
addition of another molecule to the critical cluster. Cnc is sharply increases depending on the C0/S0. The C0/S0 where Jnc ≈
determined by the energy barrier for nucleation (∆Gnc) as: 1 is defined as the critical supersaturation ratio (CSSR). No
(36) nucleation occurs where C0/S0 < CSSR in the time range of
oral absorption. The concentration range of S0 < C0 < S0 ×CSSR
 ∆G nc  is called metastable zone. CSSR is mainly determined by g.
C nc = (N A ⋅ C 0 ) ⋅ exp  -  ⋅ Z ch
 kB ⋅T  Equation 42 is the theoretical equation for homogeneous
precipitation. For heterogeneous nucleation, which is more
where NA is Avogadro number, C0 is the concentration of popular than homogeneous precipitation, the lump constant
free monomer (mol/L), kB is the Boltzmann constant, T is (b) of the foreign particle number, sticking provability, etc
temperature and Zch is the Zel’dovich number. NA·C0 is the an apparent surface energy (g¢) is introduced [107]:
concentration as the number of molecules per volume. ∆Gnc
is expressed as (spherical nuclei assumed): (43)
1/ 2
(37) 2 k T 
J nc = b ⋅ D mono ⋅ (N A ⋅ C 0 ) ⋅  B 
16p ⋅ g 3 ⋅ v m 2  g 
∆G nc =  16p  g'  3   
2
3 ⋅ (k BT ⋅ ln (C 0 / S 0 ))
2
vm
ln (C 0 / S 0 )⋅ exp  -     
where g is surface energy, and vm is the molecular volume.  3  k BT   ln (C 0 / S 0 ) 
Zch is expressed as:
7.2 Application of CNT for COAS
(38) After dissolution of salt form API, nucleation of free form occurs
(k BT )3 / 2 (ln (C 0 / S 0 ))
2
when C0/S0 in the GI tract exceeds CSSR (Section 6.2.2). It is
Z ch = . worth noting that the concentration in the GI tract is also
8p ⋅ g 3 / 2 ⋅ v m
affected by the permeability.
The frequency of collision is determined by the critical Usually, nucleation and growth occur simultaneously,
radius of critical nuclei (rp,nc), Dmono and the interfacial reaction resulting in dispersed particle size of the precipitant. To
rate correction factor (jnc) as: simulate the precipitation process, a particle bin should be

Sugano
Monomer Dimer Trimer i-mer 8. Permeation: absorption into body
In this section, a theoretical scheme to represent the intestinal

membrane permeation is discussed. First, the effective concen-
10 tration for permeation is defined considering various molecular
states of a drug in the GI fluid (Section 8.1). Then, the
8 Critical nuclei radius relationship between kabs and the effective intestinal membrane
“Surface energy”
6 permeability (Peff) is discussed (Section 8.2). Peff is then reduced
“Volume”
4
to more intrinsic parameters, considering the morphology of the
Total free energy
intestinal tube and the permeation pathways (Section 8.3 – 8.5).
2 Physiological parameters and acquisition of drug parameters are
discussed in Section 8.6 and 8.7, respectively.

∆G
0
0 5 10 15
-2 8.1 Effective concentration for permeability
-4 The definition of Peff is based on the effective concentration
for permeation in the GI tract (Cperm) (Figure 3) and the
-6 smooth intestinal tube surface (Figure 8A) (the effect of the
-8 GI morphology on Peff is discussed in detail in Section 8.3).
Cperm is the sum of the concentration of molecular state
-10
that can permeate the first permeation barrier, the unstirred
water layer of the intestinal membrane (mUWL) that partly
Figure 7. Free energy – cluster size relationship. superimposes on the mucus layer. It was suggested that a
particle of < ∼ 500 nm diameter can permeate the mucus layer
(Figure 3) [112-114]. Therefore, free monomer, bile micelles
created as nucleation occurs. This particle bin works in bound molecule, nano scale API and formulation particle
the same way as that for the dissolution of API particles (< ∼ 500 nm) are considered to be effective for Peff calculation.
(Section 6.4). The initial radius of a particle created by Consequently, the sum of the compound amount available for
nucleation can be given by Equation 40. Once a particle bin mUWL permeation (Xperm) and Cperm can be defined as:
with an initial particle radius is created, the particle growth
is represented by Equation 18 for a free form (with negative (45)
concentration gradient) (Section 6.2.1). X perm = (X mono + X bm ) + X API (< 500nm) + X fm (< 500nm )
7.3 Acquisition of drug parameters = X dissolv + X others

b and g¢ are the drug parameters for nucleation. The g¢ value
is very difficult to measure and is usually not available in (46)
drug discovery. Therefore, it would be practical to estimate X perm
C perm =
g¢ from measured CSSR [106,108,109]. Another unknown drug VGI
parameter, lprec, can be obtained from the precipitation
growth rate using a seed nuclei under metastable zone (47)
concentration [106]. In addition, the g¢ and b values can
be obtained by simulation fitting to in vitro precipitation f dissolv + f others = 1
experiment data, which mimic the fluid transfer from the where VGI is the GI fluid volume, fdissolv is the fraction of
stomach to the small intestine [110,111]. the sum of monomer and bile micelle bound molecule, and
A calculation scheme for g from solubility has been fother is the fraction of nano scale API and formulation par-
reported [106]: ticles. In most cases, it would be appropriate to assume
that only free monomer can permeate the epithetical
(44) membrane (Figure 3) [115-117].
k BT   S 
g= . 0.33 .  -ln  0   8.2 Peff and absorption rate
(v m /N A )2/3
  55.6  
Peff is the clearance per surface area of the intestinal tube
However, the estimation is not accurate enough (assuming a smooth tube, Figure 8A). Permeation clearance
considering the strong sensitivity of CSSR against g. In addi- (CLperm) = Peff × SAGI (SAGI: the surface area of the intestine
tion, this value is for homogeneous nucleation. CSSR can be (as a smooth tube)) [118,119]. The relationship among kabs,
measured by a pH titration method or precipitation CLperm and intestinal fluid volume (VGI) corresponds to that
experiments [106,108]. among the elimination rate (kel), clearance (CL) and the

A. B. Agitation
1.0 – 1.7 cm
PmUWL
Plicate
Peff mUWL
Pplicate
mUWL
0.07 cm (0.7 mm)

Agitation
P
Villi ep
Blood flow
P P
pli ep
ca
te
C. D.
+
O NH
O N
Undissociated OH
OH H H Dissociated
NH NH
pKa Ppara Ptrans Pactive

+ H
NH N
0.0000006 cm (6 nm)
- - H - -
OH OH
0.0018 cm (18 µm)

O
NH NH
NH NH
O O
OH OH
- - NH H -
N+ -
H
+
O NH O N
OH OH H H
NH NH
Figure 8. Morphology of human small intestinal and permeation pathways
volume of distribution (Vd) in pharmacokinetics (kel = CL/Vd). (49)

The relationship among Peff, kabs and the absorption rate DF = f (VGI )
(dXabs/dt) is expressed as:
(50)
(48) SAGI = f (VGI ).
dX abs For cylindrical tube, DF = 1 and SAGI/VGI is:

= (Intestinal surface area ) × (Permeability ) × (Concentration )
dt
SA 2
(51)
= SAGI ⋅ Peff ⋅ C perm = GI ⋅ Peff ⋅ VGI ⋅ C perm = DF ⋅ ⋅ Peff ⋅ VGI ⋅ C perm
VGI R GI , SAGI 2pR GI ⋅ LGI 2
= =
=
Peff ⋅ SAGI
⋅ X perm =
CL perm
⋅ X perm = k abs ⋅ X perm
VGI pR GI 2 ⋅ LGI R GI
VGI VGI
where LGI is the length of the GI tract. However,
where DF is the degree of flatness of the intestinal tube the intestinal tube is rather flat and DF should be > 1
representing the deviation from the cylindrical tube and (Section 8.6) [120,121].
RGI is the GI tract radius. When the dimension is considered,
the upper and lower expressions of Equation 48 are 8.3 Effect of plicate and villi structures
equivalent (based on concentration and amount, respec- 8.3.1 Plicate structure
tively). Theoretically, both DF and SAGI are the functions Peff value is usually calculated assuming that the small intestine
of VGI. has a smooth surface. However, the human small intestinal

Sugano
tube has a plicate and a villi structure (Figure 8A) [17,18]. The nano scale API and formulation particle (< ∼ 500 nm) are
mUWL is adjacent on the villi top (Figure 8B). Therefore, considered to be effective for Peff calculation [115,125,126]. In
Peff can be expressed as Equation 52: addition to diffusion, water conveyance would also affect
mUWL permeation [127,128]. PUWL can be expressed as
(52) Equation 55 [121]:
Peff = Pplicate ⋅ PE
(55)
where Pplicate is the plicate surface permeability and PE is
plicate expansion. D × f mono + A '× Dbm × f bm 
PUWL = f dissolv ×  mono + PWC  + f others × Pothers
 hmUWL 
8.3.2 Villi structure
where A′ represents the interaction between the mucus layer
The plicate permeability is the tandem process of mUWL

permeation and epithelial membrane permeation (Figure 8B). and bile micelles. It was suggested that when the
After passing through the mUWL, only the fraction of free total bile micelle concentration is lower than 2.5 g/dl,
monomer molecules (fmono) in the fraction of dissolved mol- A¢= ∼ 3 [125].
ecules (i.e., fmono × fdissolv) can pass across the epithelial mem- mUWL permeation of nano particles and emulsions
brane (Figure 3). Pplicate can be expressed as Equation 53: (represented as Pothers) has many unknown factors and is
now under extensive investigation (Sections 10.1 and 10.2).
(53) The mucus layer is a negatively charged polymer
matrix [129,130]. Therefore, the mucus layer permeation
1 1 1
= + depends on the particle size and the surface charge of the
Pplicate PUWL f mono ⋅ f dissolv ⋅ Pep ⋅ Acc ⋅ VE
particle [112,114,131]. Particles smaller than ∼ 500 nm may
where PUWL is the mUWL permeability, Pep is the epithelial pass through in the mUWL [112-114,129]. In addition to the
membrane permeability of monomer (unbound) molecules, particle size and surface charge, surface hydrophobicity
Acc is the accessibility to the villi surface and VE is the villi would also affect the mucus layer permeability of nano
expansion. Because mUWL and epithelial membrane per- particles [114].

meations are sequential, the sum of the reciprocals becomes
the reciprocal of Pplicate. (Permeability is the reciprocal of 8.5 Epithelial membrane permeability
permeation resistance. The total resistance of multiple Pep can be further deduced to passive transcellular (Ptrans),
resistances in sequence is calculated as the sum of each active transcellular (Pactive) and paracellular pathways (Ppara)
resistance; refer Ohm’s law.) fmono contains both dissociated (Figure 8C). Because these permeation pathways are parallel,
and undissociated species (Equations 12 and 58). Acc depends Pep can be expressed as the sum of Ptrans, Ppara and Pactive as
on the diffusion coefficient and the epithelial membrane Equation 56:
permeability. In the case of a high Pep drug, drug molecules
are absorbed from the top of the villi before they diffuse to (56)
the crypt of the villi, whereas in the case of a low Pep drug,
Pep = Ptrans + Ppara + Pactive
the drug molecules can diffuse to the crypt and utilise the
whole villi surface for permeation. The detailed calculation
scheme of Acc has been reported previously [122,123]. The Acc 8.5.1 Ptrans permeation: pH partition theory
value is ∼ 0.4 – 1 range. The cellular membrane mainly consists of phospholipids
and cholesterol ([14] and references therein), and is the per-
(54) meation barrier for hydrophilic molecules (Figure 8D). In the
(
Acc = f Pep , Deff , PWC , villi size ) case of weak acids and bases, undissociated species are much
more permeable than dissociated species. The fraction of
where PWC is mUWL permeation by water conveyance. undissociated species depends on the pH near the epithelial
Pplicate can be roughly categorised as mUWL limited or membrane surface (microclimate pH, lower than the bulk
epithelial membrane limited. In the case of many hydrophilic fluid pH) [132] and the pKa of the drug. Ptrans can be
compounds (approximate octanol–water distribution coefficient represented as the sum of the passive transcellular permea-
at pH 6.5 (logKoct,pH6.5) < 0), it is the epithelial membrane bility values of each molecular species and their fraction
limited, whereas it could be mUWL limited for many lipophilic as Equation 57:
compounds (∼ logKoct,pH6.5 > 1.5).
(57)
8.4 Unstirred water layer permeability
Ptrans = f 0 ⋅ Ptrans ,0 + f + ⋅ Ptrans , + + f − ⋅ Ptrans , −
mUWL partly superimposes to the mucus layer
+ f + + ⋅ Ptrans , + + L = ∑ f z ⋅ Ptrans ,z
(Figure 3) [124]. Free monomer, bile micelles bound molecule,

(58) (64)
f 0 + f + + f − + f ++ L = ∑ f z = 1
(
RK (R ratio )= (1- R ratio )2 1- 2.104 × R ratio + 2.09 (R ratio ) - 0.95 (R ratio )
3 5
)
where fz is the fraction of each charged species (z: charge
number) calculated from pKa, and Ptrans,z is the permeability (65)
of z charged species (Ptrans,0 is the intrinsic passive transcel-
Z para ⋅ z
lular permeability of uncharged species). According to the E (z ) =
pH partition theory, permeability of dissociated species can (
1 − exp -z para ⋅ z )
be neglected. Therefore, Equation 57 can be simplified as
where Rratio is the ratio of the apparent pore radius of the
Equation 59:
paracellular pathway (Rpara) and the molecular radius of a
permeant (rmono) (Rratio = rmono / Rpara), and A” is a lump
(59)
constant of paracellular pathway population etc. Zpara corre-
Ptrans = f 0 ⋅ Ptrans ,0 . sponds to the apparent electric potential of the paracellular
However, recently, it was suggested that monocationic pathway (for the intestine, 18 – 80 mV). RK is called Renkin
molecules can permeate the lipid membrane by the aid of endo- function and it decreases as the molecular radius of a permeant
genous anionic phospholipids [133-135]. f0 can be calculated as: increases. In addition to the molecular size and charge, the
paracellular pathway permeability was suggested to be
(60) affected by the substrate’s lipophilicity [145,146].
1 Active transport
f0 = for monoprotic base 8.5.3
1 + 10 pK a − pK Simulation of active transport is under extensive investigation
(Section 10.5). Usually, permeation (both influx and efflux)
(61) by active transport depends on the concentration of a drug:
f0 =
1
for monoprotic acids
(66)
1 + 10 pH − pK a J max
Pactive =
where pKa is one of the most important physicochemical K m + C active
properties that affects the membrane permeability. One unit where Jmax is the maximum flux, Km is the Michaelis–Menten
difference of pKa (or pH) results in a 10-fold difference of constant and Cactive is the effective concentration for active
Ptrans. By combining Equations 52, 53, 55, 56 and 59, we transport. Km is based on the experimental concentration
obtain Equation 62: and should be aligned with the definition of Cactive [147,148].
8.5.2 Ppara
8.6 Physiological parameters
The Ppara is permeation through the tight junction between
PE = ∼ 3 in humans, whereas PE = ∼ 1 in rats and dogs
the epithelial cells (Figure 8D). The tight junction is main-
because of the lack of the plicate structure [17,18].VE was
tained by the cell adhesion molecules and is negatively
reported to be 10 for humans and dogs, and 5 – 7 for
charged [136]. Cationic small molecules (MW < 200 – 400
rats [17,18,149]. Villi height is ∼ 600 – 700 µm [23,123]. PWC is
for humans) tend to permeate the Ppara, whereas large and/or
∼ 0.23 × 10-4 cm/sec for humans [121,127,150-153] and lesser
negatively charged molecules cannot. Permeation through
for rats [153]. Considering the plicate expansion, the effective
the Ppara has been successfully modelled as the permeation
mUWL thickness on Pplicate bases is ∼ 300 µm (calculated
through a tube with a negatively charged wall [27,137-144]:
from the hmUWL values of ∼ 100 µm on Peff bases (smooth
tube based)) [118,154]. The thickness of the mucus layer is
(63)
∼ 150 µm (rat small intestine) and 800 µm (rat colon). RGI
Ppara = f 0 ⋅ Ppara,0 + f + ⋅ Ppara, + + f − ⋅ Ppara, − + f + + ⋅ Ppara, + + K is ∼ 1.5 – 2.5, 0.5 and 0.2 cm for humans, dogs and rats,
1 r  z (z ≠ 0)  respectively [24,119].
= A ''⋅ ⋅ RK  mono   f 0 + ∑ f z ⋅ E (z ) DF was suggested to be ∼ 1.7 for humans (calculated
rmono  para  
R 
from the oral absorption of a low permeability compound
(62)
1
Peff = ⋅ PE
1 1
+
f dissolv
 D mono

⋅ f mono + A '⋅ Dbm ⋅ f bm 
+ PWC  + f others ⋅ Pothers
( )
f dissolv ⋅ f mono ⋅ f 0 ⋅ Ptrans ,0 + Ppara + Pactive ⋅ Acc ⋅ VE
h iUWL 

Sugano
assuming that colonic absorption is negligible) [121]. This the intestinal membrane surface); iv) calculate Pep by
value is higher than the theoretical value for the cylinder adding in vivo paracellular pathway permeability; v) multiply
shape (DF = 1), suggesting that the intestine is rather for the free fraction; vi) multiply for the villi structure; vii)
flat [155]. correct for villi surface accessibility; viii) add the in vivo
Gotch et al. reported that the total water volume in the mUWL effect; and ix) multiply for the plicate structure
human small intestine was 212 ± 110 ml [19]. Recently, (physiological parameters for iii) – ix) differ depending on a
Schiller et al. reported that the free water volume in water GI position and animal species).
pocket measured by water-sensitive magnetic resonance When logKoct,pH6.5 > ∼ 2 – 3, as Pep would be significantly
imaging was 105 ± 72 ml [156]. However, this value might higher than PUWL, mUWL permeation would be the rate
not be the real total volume available along the intestine, as limiting step of intestinal membrane permeation and the Pep
only the free volume in the water pocket was counted [157]. estimation error would have little effect on Peff [121,168,169].
BCS uses 250 ml [158]. The same volume was also used to Therefore, in many cases of logKoct,pH6.5 > ∼ 2 – 3, rough
simulate the dose-dependent absorption of gabapentin by estimation of Pep by logKoct,pH6.5 might be appropriate. When
active transport [147]. in vitro membrane permeability is to be used to estimate Peff
The microclimate pH is maintained to be lower than the for logKoct,pH6.5 > ∼ 2 – 3 cases, experimental conditions should
luminal fluid pH and is pH 5.2 – 6.9 [13,132]. be carefully considered and the data should be meticulously
The effective width of the paracellular pathway is different interpreted. The in vitro mUWL is much thicker than
for each animal and GI position. The paracellular pathway in vivo mUWL under a standard agitation condition [170].
is leakier in dogs than in rats and humans [159-161]. Caco-2 Experimental artifacts such as membrane binding should be
cells have tighter tight junctions than the human small carefully investigated. To avoid underestimation of membrane
intestine [162,163]. permeability in logKoct,pH6.5 > ∼ 2 – 3 compound cases [171-173],
several improvements of experimental conditions have been
8.7 Acquisition of Peff value: theoretical proposed. To obtain appropriate Pep values of high permea-
in vitro–in vivo extrapolation bility compounds, the effect of mUWL should be removed by
It is practically impossible to directly measure a Peff value in increasing the agitation strength [174]. An appropriate Pep value
humans in drug discovery. Single pass perfusion studies in can be also obtained from the pH permeability profile in the
rats can be used to estimate Peff in humans. Rat Peff was case of a dissociable compound [175,176]. Addition of bovine
found to correlate well with human Peff [164,165], although serum albumin or surfactant in the acceptor (basolateral)
the absolute value of rat Peff is 5 – 15 times lower than compartment can mimic the sink concentration of in vivo
that in humans, as plicate and villi expansions are smaller intestine [13,171,172,177-179]. In addition to the difference of
in rats than in humans [164,165]. However, the fraction in vitro and in vivo systems, experimental artifacts, for exam-
of a dose absorbed (Fa) in humans and rats are very ple, nonspecific binding to instruments and precipitation in
close for permeability limited absorption [159]. Because the the donor compartment should be carefully checked for low
intestinal tube radius is in the denominator of the Equation solubility/high lipophilicity compounds [170,172-174,179-181].
48, 2DF/RGI is larger in small animals (surface area:volume In silico estimation of Ptrans,0 has been investigated [175,182,183].
ratio becomes larger as an object becomes smaller). The Ptrans,0 can be roughly estimated by logKoct,0 as [121]:
decrease of Peff in rats is cancelled out by the increase of
2DF/RGI to give a similar kabs and Fa between rats and (67)
humans. The same principle can be applied for dogs except
Ptrans ,0 (cm / sec ) = 2.36 × 10 −6
K oct ,01.1.
for paracellular pathway permeants.
Peff can be estimated from in vitro assay data, such as
Caco-2 [166] and the parallel artificial membrane permeation 9. GI transition: mathematical expression of
assay (PAMPA) [13,140,167]. However, with a widely used GI transition
experimental condition, the mUWL thickness, the sink con-
dition in acceptor compartment, the paracellular pathway, 9.1 Compartmental models
active transporter expression level, etc are not the same as The GI tract should be divided into at least three
that of the in vivo intestine. Therefore, theoretical correc- compartments, the stomach, the small intestine and the
tions for these effects are important. The theoretical Peff colon, to reflect the significant difference of physiological
estimation process for passive permeation can be to [168]: i) conditions in these sections of the GI tract (S1I1C1 system,
calculate in vitro Ptrans,0 from apparent in vitro membrane mixed tank model. S = stomach, I = small intestine, C = colon.
permeability data by removing the effect of in vitro mUWL, The number indicates the compartment number) [94,184].
paracellular pathway permeability and applying the pH The transit kinetics could be zero order, first order, etc., to
partition theory; ii) calculate in vivo Ptrans,0 from in vitro represent the observed GI transit profile. Despite of its
Ptrans,0; iii) calculate the Ptrans by applying the pH partition simplicity, the predictability is appropriate for many cases
theory to Ptrans,0 (considering the in vivo microclimate pH at and has been used in the literature [30,31,94,185].

To represent the regional differences of the GI tract, fluid. A similar approach was taken by Willmann
several compartments can be assigned for the small intestine. et al. [193,194].
Yu et al. determined that the optimal compartment number
with first order transit was seven, based on the best fitting 9.3 Mass balance of dissolved drugs in a GI position
to the colon exit time distribution [186,187]. However, it The mass balance of dissolved drug in the GI fluid at
should be stressed that the real small intestine is, of course, not a GI position (subscript k) can be mathematically expressed
explicitly physiologically divided into these compartments. as Equation 70:
Therefore, this model is not a physiological model as in
the same sense of the physiologically based pharmacokinetics (70)
model. The movement of particles by S1I7C1 system is dX dissolv , k
= (K t , k −1 ⋅ X dissolv , k −1 − K t , k ⋅ X dissolv , k ) +
shown in Figure 9. It is suggested that drug particles dt
disperse widely in the small intestine at 120 min. The  i . j dX API ,ij , k i ', j '
dX NFP ,i ' j ' k  dX abs , k
merit of S1I7C1 system is that it easily enables simulation  ∑ + ∑ −
of the physiological differences in each small intestinal  if GIPij = k dt if GIPi ' j ' = k dt  dt
position such as pH, bile concentration and transporter The first parenthesis represents the flow-in of dissolved
expression level. Advanced compartment absorption model [25], drug from the previous position and flow-out into the next
GI transit absorption model [188-190], advance dissolution position. The second parenthesis represents the dissolve-in
absorption and metabolism model [191], etc., have been and precipitate-out of the dosed API particles (XAPI) and
previously reported. newly formed precipitant particles (XNFP). The last term
As discussed in Section 6, to represent the movement of represents absorption into the body. GIPij represents the GI
each particle and the particle size reduction accompanied position of a particle bin ij at time t.
with dissolution, a particle size bin (represented as i) has to
be further divided into virtual particle bins (represented as j). 9.4 Physiological parameters relevant to GI transit
If the particle size distribution is represented by 20 particle The stomach emptying time in the fasted state human is
size bins and 100 virtual particle bins are assigned to each ∼ 15 – 30 min and much slower in the fed state [17,18,195].
particle size bin, a total of 2000 particle bins are required. The small intestinal transit time is ∼ 3.5 h in humans, 2 h
Because each particle group has one differential equation for in dogs and 2 – 3 h in rats [17,18].
dissolution, 2000 differential equations are required. How-
ever, with today’s high-speed computers, this number is not an 10. Extension: drug delivery systems, food
issue. The GI transit of drug particles can be represented as: effects and biological processes
(68) In this section, advanced applications of COAS are discussed.

The subjects discussed in this section have many unknown
dN API ,GI , k
= −K t , k ⋅ N API ,GI , k factors and are now under extensive investigation. Therefore,
dt when performing COAS, it is necessary to collaborate with
where NAPI,GI,k is the number of API particle bins in subject matter experts.
the GI position k, and Kt,k is the first order transit rate
constant (= compartment number/mean transit time Tsi). 10.1 Nano scale API particle
The particles of newly formed precipitant can be treated Particle size of a drug substance can be reduced down
similarly by assigning a particle size bin and virtual to nano scale by several methods, for example, beads
particle group as new precipitant particles are generated milling [196,197]. As long as the solid-state of the drug
(i¢ and j¢) (Section 7.2). substance is not destroyed, these formulations show little
increase in the equilibrium solubility [198]. However, nano
9.2 Dispersion model milling could increase the oral absorption more efficiently
The dispersion model describes the transit of drugs than suggested from the solubility [196,199]. One possibility
through the continuous intestinal tube by convection and may be that nano scale API particles could potentially be
dispersion [192]: able to penetrate the intestinal mucus layer [112-114,129].
(69) 10.2 SEDDS

It was suggested that the amount of a drug dissolved as nano
∂N API ,GI (k ,t ) ∂ 2N API ,GI ∂N API ,GI
= Disp − Vc scale emulsions (or micelles) correlates with in vivo absorp-
∂t ∂2k ∂k tion [200-205]. This is in good agreement with the mUWL per-
where NAPI,GI is the particle number concentration at a meation model (Equation 55). The mathematical treatment can
position k or dissolved drug concentration, Disp is the be similar with that for bile micelles (Sections 4, 5 and 8).
dispersion coefficient and Vc is the velocity of the intestinal After administration of self emulsifying drug delivery system

Sugano
100
5 min
is important to consider the effect of bile micelles. Bile
90 micelles not only increase the solubility of a drug [212], but
10 min
Percent of particles
80 also decrease the diffusion coefficient and free fraction,

20 min
70
30 min which affect the dissolution rate and permeability (Sections 5, 6
60 60 min
50 and 8). In addition to the difference in bile micelle concentra-
90 min
40 120 min tion, the difference in stomach pH, gastric emptying rate,
30 180 min agitation strength, fluid viscosity and interaction with food
20 240 min components should be carefully considered [209,213].
10 300 min
0 360 min
1 2 3 4 5 6 7 8 9 10.5Biological processes in the GI tract: active
GI position transport and gut wall metabolism
Quantitative simulation of biological processes in the intestine

is now under extensive investigation.
Figure 9. Dispersion of drug particles represented by S1I7C1 The effects of influx and efflux transporters and metabolic
system. The GI position number is 1 to 9 corresponds to the enzymes (CYP 3A4, etc) that are expressed in the intestinal
stomach (1) and the proximal to distal small intestine (2 - 8)
wall have been extensively investigated [148,214-216]. To simu-
and colon (9).
late the quantitative contribution of these processes, in addi-
tion to the regional difference of expression level [217], drug
(SEDDS), nano scale emulsions can be produced by the lipoly- concentration in the GI tract (and in the epithelial cells)
sis of the excipients of SEDDS. Therefore, it is important to and contribution of passive permeation should be carefully
consider the effect of lipase on the produced emulsion size. considered [216,218]. The substrates for these enzymes often
An in vitro lipase digestion system was shown to be useful show good Fa when the concentration is high enough to satu-
in investigating the oral absorption from SEDDS [200,204]. rate the enzyme and/or passive permeation is rapid [219,220].
An explicit epithelial cell model (Figure 8C) will provide
10.3 Controlled release more accurate estimation of active transport and metabolic
COAS is a crucial component of controlled release feasi- processes [221,222]. These approaches have affinity with sys-
bility assessment in drug discovery and development [206]. tems biology. Estimation of the concentration in the epithe-
Convolution of in vitro release profile with dissolution, per- lial cell is the key for accurate prediction. When considering
meation and pharmacokinetic (PK) processes is often used a prodrug approach, appropriate estimation of biological
to simulate the plasma concentration time profile. Empirical processes is especially important [223].
equations such as zero order release and Weibull function For a more dynamic simulation of oral absorption, water
can be obtained from the in vitro release experiments and be absorption, GI fluid secretion and absorption of GI fluid
used for COAS [3]. component (e.g., bile acids) should be taken into account,
Release of drug particles from a controlled release especially for the fed state because the chemical composition
formulation can be modelled by calculating the release rate of of the GI fluid dynamically changes as food is digested [29].
particle bins from the formulation (Section 9). Once the par-
ticle bin is released into the GI fluid, it would be appropriate 10.6 Distribution, metabolism and excretion
to assume that the particles start to dissolve. COAS can be connected to PK models such as the one
Mechanistic mathematical calculation of release profiles, compartment model, the two compartment model and
considering water penetration into the formulation, polymer physiologically based pharmacokinetics models. After the
erosion, etc., are other interesting areas in which computational intestinal membrane permeation, the drug molecule moves
simulation would help formulation design [207]. into the portal vein and passes through the liver. Estimation
Physiological conditions in the colon should be carefully of first pass extraction in the liver (Eh) and enterohepatic
considered; for example, available fluid volume, bile concen- recirculation is important. For enterohepatic recirculation,
tration, viscosity, pH and intestinal membrane morphology [208]. accumulation in and release from the gall bladder should be
Basically, the fluid condition and membrane structure are considered (the latter would be triggered by food intake).
disadvantageous for drug absorption in the colon. Therefore,
a high solubility/high permeability compound is more suitable 11. Integration: analytical and
for absorption from the colon [206]. numerical solutions
10.4 Food effect Because Equations 18 and 48, etc., are differential equations, we
Simulation of food effect is important for drug develop- have to solve these equations to obtain simulation results, for
ment [209-211]. The physiological difference between the example, Fa. First, analytical solutions for three typical types
fasted and fed state can be considered by COAS. To of oral absorption, i.e., permeability limited, solubility limited
appropriately simulate the food effect (positive/negative), it and dissolution limited, are discussed (Section 2.1), since these

analytical solutions explicitly describe the impact of each 11.1.3 Dissolution limited case
parameter on Fa. Then, steady-state approximation of Cdissolv is In the case of dissolution limited absorption, Fa can be
applied to calculate Fa for intermediate cases. approximated to be equal to the dissolved fraction (Fd). An
Numerical integration is required to simulate the analytical solution of Equation 18 can be obtained assuming
dynamic change of the Cdissolv and the regional differences of that Cdissolv is constant over time and equals 0 (the perfect
Peff, Sdissolv, etc., in the GI tract, and to simulate the plasma sink condition). For mono-dispersed spherical particles,
concentration time profile. Numerical integration is discussed Equation 18 can be rewritten as [94]:
after analytical solutions.
(74)
11.1 Analytical solutions dX API p 3 ⋅ D eff ⋅ S surface
To derive analytical solutions, the one compartment model =− ⋅ X API ,t = 02 / 3 ⋅ X API 1 / 3rp ,t = 0 < 30 mm
rp ,t = 02 ⋅ r
dt
of the small intestine (S0I1C0 system) is assumed (no regional
difference in GI tract).
(75)
11.1.1 Permeability limited case
dX API p 3 ⋅ D eff ⋅ S surface
In the absence of solubility/dissolution limitations (instant =− ⋅ X API ,t = 01/ 3 ⋅ X API 2 / 3rp ,t = 0 > 30 mm .
and complete dissolution), analytical solutions of Equation dt h pUWL ,t = 0 ⋅ rp ,t = 0 ⋅ r
48 can be obtained as [187]: By separation of variables, the analytical solutions are
given as:
(71)
 2DF  (76)
Fa = 1 − exp (-k abs × Tsi ) = 1 − exp  - × Peff × Tsi 
 rGI   2 ⋅D ⋅S 
3/2
surface ⋅ Tsi
Fa ≈ Fd = 1 − 1 − eff  rp ,t = 0 < 30 m m
Because colonic absorption of low permeability compounds  rp ,t = 02 ⋅ r 
 
is usually limited [208,224], Tsi can be set to the small intestine

transit time.
(77)
11.1.2 Solubility limited case (MAD) 3
Maximum absorbable dose maximum absorbable dose  D eff ⋅ S surface ⋅ Tsi 
Fa ≈ Fd = 1 − 1 −  rp ,t = 0 > 30 m m .
(MAD) [225,226] and maximum Fa can be calculated by inte-  rp ,t = 02 ⋅ h pUWL ,t = 0 ⋅ r 
 
grating Equation 48 assuming that Cperm is constant over
time and equals Sdissolv as Equations 72 and 73: When further assuming XAPI,t=02/3. XAPI1/3 ≈ XAPI,t=01/3.
XAPI2/3 ≈ XAPI:
(72)
2 × DF
(78)
MAD = kabs × Sdissolv × VGI × Tsi = × Peff × Sdissolv × VGI × Tsi
RGI  3 ⋅ Deff ⋅ Ssurface 
Fa ≈ Fd = 1 − exp  − ⋅Tsi  rp ,t = 0 < 30 mm
 r p ,t = 0 ⋅ r 
(73)
MAD (79)
Fa =
Dose
(if Fa>1 then Fa =1).
 3 ⋅ D eff ⋅ S surface 
Because colonic absorption of low solubility compounds Fa ≈ Fd = 1 − exp  − ⋅ Tsi  rp ,t = 0 > 30 mm .
 rp ,t = 0 ⋅ h pUWL ,t = 0 ⋅ r 
is usually limited, Tsi can be set to the small intestine transit
time. It is clearly shown in Equations 72 and 73 that, in the As hpUWL < hpUWL,t=0 and XAPI < XAPI,t=0, Equation 78
case of solubility limited absorption, Fa depends on Peff as underestimates the dissolution profile. It is clearly shown in
well as Sdissolv and Dose; however, it does not depend on the Equations 76 – 79 that, in the case of dissolution limited
particle size. absorption, Fa depends on rp, Deff and Ssurface; however, it
MAD calculation assumes that oral absorption is not does not depend on Peff and Dose.
dissolution limited and there is no supersaturation in the GI
tract. MAD calculation is appropriate for undissociable and 11.1.4 An, Do and Dn
free acid compounds, whereas it is not appropriate for free Dimensionless parameters of absorption number (An), dose
base compounds and the salts of acid and basic compounds, number (Do) and dissolution number (Dn) have been
as supersaturation can occur in the GI tract. In addition, introduced to simplify the calculation [187,227]. The An is
MAD calculation is not appropriate for large API particles. defined as:

Sugano
(80) (86)
2DF 2 ⋅ DF 3 ⋅ X API ,t = 0 ⋅ D eff
An = ⋅ Peff ⋅ Tsi = k a ⋅ Tsi . ⋅ Peff ⋅ C dissolv ,ss ⋅ VGI =
R GI R GI rp ,t = 0 ⋅ h pUWL ,t = 0 ⋅ r
This definition of An is different from the original The left hand side is the absorption rate equation and the
definition [227]. However, for simplicity of the following right hand side is the dissolution rate equation. These two
discussion, Equation 80 is used in this article. Using equations are equalled as dissolved-in speed and absorbed-out
Equation 80, Equation 81 can be rewritten as: speed are balanced. By rearranging and using An, Dn and
Do, we can obtain a dimensionless parameter that represents
(81) the degree of saturation (saturation number, Sn):
Fa = 1 − exp (-An ).
(87)
Equation 83 can be rewritten as Equation 82 [227]: C dissolv ,ss 1
= Sn =
S dissolv An
(82) 1+ .
Dn ⋅ Do
S × VGI An
Fa = dissolv ⋅ An = Using Sn for Equations 73 and 78, we obtain:
Dose Do
(88)
(83)
An 1
Fa = × Sn =
Dose Do 1 Do
Do = . +
S dissolv × VGI Dn An
When similar conversion was applied for dissolution

(89)
limited absorption, Equation 78 can be converted to

Equation 84:
Fa = 1 − exp (−Dn (1 − Sn ))
(84)  
 1 
Fa =1- exp (-Dn ) = 1 − exp  − If Do < 1, Do = 1.
1 Do 
 + 
Dn An
(85) This correction reduced the discrepancy between the
3 ⋅ D eff ⋅ S surface
analytical solution and numerical integration (Figure 10,
Dn = ⋅ Tsi . bold line). Equation 88 slightly overestimates Fa whereas
rp ,t = 02 ⋅ r
Equation 89 slightly underestimates Fa. The remaining slight
difference would be due to the assumption of steady-state
11.1.5 Steady-state approximation for Cdissov concentration and the transit of particles along the GI tract.
Fa by analytical solution can be obtained by taking the It should be noted that these analytical solutions (Equations
minimum Fa values for the three rate limiting scenarios. 81, 82, 84, 88, and 89) have several conditions for applicable
As shown in Figure 10, at high and low ends of dose compound characteristics, that is, undissociable drugs and free
and particle size, the analytical solution is in good acidic compounds. However, considering the convenience and
agreement with the numerical solution in the S1I7C1 clarity of the analytical solution and that many low solubility
system. However, in the intermediate range, the discrepancy compounds are undissociable, the analytical solution would
was large. be beneficial enough for drug discovery. Figure 10 suggests
In the intermediate range, the assumption used for the that the differences between the GI compartment models
above analytical solutions, that is, Cdissolv = 0 in Equation 18 (S0I1C0 versus S1I7C1) and between the analytical and
(sink condition for dissolution equation) and Cdissolv = Sdissolv numerical solutions (analytical and Runge–Kutta 4th; next
in Equation 48 (saturated concentration for absorption section) have little effect on the simulation results. Sn can be
equation) is not appropriate. To calculate appropriate Cdissolv, used to indicate whether the oral absorption of the drug
it can be assumed that Cdissolv becomes a steady value is dissolution limited (sink condition, e.g., Sn < 0.3) or
(Cdissolv,ss) when the dissolution rate and permeation rate solubility limited (e.g., Sn > 0.9).
balance (Section 9.3). In the initial phase of oral absorption,
XAPI ≈ XAPI,t=0 (= Dose). When we assume Ssurface = Sdissolv 11.2 Numerical integration technique for COAS
(valid for undissociable compounds and the low S0 cases of As an integration algorithm, Runge–Kutta 4th is most
dissociable compounds): commonly used because of a good balance between

Dissolution rate limitied
Permeability limited
Solubility limited
Steady Cdissolv
Numerical integration with

S1I7C1 system
A. 100 B. 100
90 90
80 80
70 70
60 60
Fa %
Fa %
50 50
40 40
30 30
20 20
10 10
0 0
1 10 100 1000 1.00 10.00 100.00 1000.00
Dose (mg) Particle diameter (µm)
Figure 10. Comparison of analytical solution for S0I7C0 and numerical solution for S1I7C1 system. Undissociable compound,
Peff = 1 × 10-4 cm/sec, Deff = 5 × 10-6 cm2/sec, Sdissolv = Ssurface = 0.1 mg/mL, r = 1.2 g/cm3, Tsi = 3.5 hours (Kt = 2 hour-1),
VGI = 250 mL (36 mL in each compartment), DF = 1.7, RGI = 1.5 cm, PSF = 1. hpUWL was calculated by the Hintz-Johnson model
with hHJ = 30 µm. Runge - Kutta 4th with 1 min interval was used for numerical integration. (A) Dose dependency. Particle
diameter = 50 µm (monodispersed particle). (B) Particle size dependency (monodispersed particle). Dose = 100 mg.
integration speed and accuracy. A detailed explanation of oral absorption simulation is performed. The dissolution
Runge–Kutta 4th and Euler method (the simplest one) can rate (dXAPI,ij/dt) can spread over 15 orders, as the
be found elsewhere. particle size range can be from 1 to 500 µm and the
(The following part of this section is about computational solid surface solubility can range from 0.01 to 10 mg/ml.
techniques of numerical integration. The reader is assumed In addition, the dose strength can range from 0.0001 to
to have some knowledge of numerical integration.) 1000 mg/kg (for toxicokinetics simulation). At the highest
To avoid the erratum and unstable simulation in COAS, range of the dissolution rate, in an integration interval
special treatment is required for the numerical integration of (e.g., 1 min), more than all dosed compounds could be
the NBE. The erratum simulation can be caused by overes- dissolved (an error of undissolved amount being negative)
timation of a dissolved amount in an integration interval or Cdissolv could exceed the maximum concentration in
(∆t). A decrease of an undissolved drug amount in an the GI tract (Section 9.3). Rather than by reducing ∆t
integration interval is represented by the Euler method as: (this reduces dXAPI,ij/dt × ∆t and avoids over dissolution;
however, at the same time, this increases the integration
iteration (= simulation duration/∆t) and increases the
(90)
computational time), this problem can be simply solved
dX API , ij
X AP I ,ij ,t + ∆t = X A PI , ij ,t + × ∆t by considering the meaning of the NBE in oral absorption.
dt
Over reduction of undissolved compound can be
 
= X API , ij ,t +  −SA API , ij ,t ⋅
D eff S
( )
⋅ s urfac e ⋅ S dissolv − C disso lv ,t  easily avoided by inserting one conditional equation that
 h p UW Lij ,t S diss olv  adjusts the dissolving amount equal to the remaining
× ∆t undissolved amount. Over-reaching of solubility can be
adjusted similarly. By this procedure, the simulation matches
where ∆t is the integration interval. By the iterative the permeability or solubility limited cases and the simulation
calculation of this equation (together with Equation 70), becomes appropriate.

Sugano
12. Application: Prediction process step and 12.2.2BCS class II: solubility/dissolution rate
BCS based approaches in drug research limited absorption
In the case of dissolution rate limited absorption (i.e., relatively
12.1 Prediction process step large particles and low dose), Equation 18 and its parameters
The word ‘in silico simulation’ has a wide meaning. For are important. In the case of solubility limited absorption
convenience of discussion in this article, the prediction process (i.e., relatively small particles and high dose), Equation 48
step (PPS) is roughly categorised by the available input data as: and its parameters are important.
COAS of undissociable and free acid drugs are simpler
• PPS I: Chemical structure only (in silico in a narrow sense) compared to others, because dissolution and precipitation
• PPS II: PPS I + in vitro data in the stomach and precipitation in the small intestine
A - Simple in vitro data (e.g., solubility, Caco-2) can be negligible. The prediction error was reported to be
B - Complex in vitro data (e.g., dissolution test, ∼ ± 16% (Table 1) [31], for BCS II (undissociable compound/free
intestinal perfusion) acid), when dissolution test data were available (therefore, by
• PPS III: PPS II + in vivo animal data PPS IIB prediction).
• PPS IV: PPS III + human data As discussed in Section 7, the quantitative simulation of
precipitation processes is still difficult. Therefore, prediction for
Overall prediction error is the multiple of the error in basic compounds, their salts and salts of acids are more difficult
each prediction step (Figure 2). Predictability depends on the than those for undissociable and free acid drugs. Solubility
quality and quantity of available data and the compound enhancing formulations would also be more difficult.
characteristics. PPS I has a maximum prediction error, For PPS III strategy, rats should not be used because of
whereas PPS IV would have a minimum error. the large difference in bile concentration and stomach pH.
PPS I and IIA predictions are mainly used at the Dogs would be more appropriate with some modification of
drug discovery stage. PPS IIB and III are mainly used at GI physiology such as stomach pH [41,42]. An intestinal
the early development stages. PPS IV is used at the late perfusion study using the bile micelle media (and the aggre-
development (after Phase I study) and product enhancement gates from the formulation such as micelles) would be of
stages. COAS should be aligned with the experimental great benefit to obtain appropriate Peff values [229]. Caution
screening strategy. about Peff estimation from in vitro data for low solubility
In some reports [166,228], it was suggested that a parameter compounds is discussed in Section 8.6.
refinement process using preclinical in vivo data was
performed before the prospective prediction of clinical 12.2.3 BCS class III: permeability limited absorption
oral absorption (therefore, PPS III prediction). The require- Fa prediction by PPS I ([230] and references therein), PPS II
ment of the fitting process suggested that the former pro- (e.g., Caco-2 [231] and PAMPA [14,232-234]), PPS III (rat Peff [165],
spective simulation by PPS I – II needed further improvement rat Fa [159]) and PPS IV (human Peff) [117] has been reported.
and the errors by PPS I – II were masked by using a An analytical solution for permeability limited absorption
fitting process. Therefore, those reports did not suggest (Equation 71) was mainly used to calculate Fa. Correction
that the simulation program was validated for PPS I and for the Ppara is important for improving prediction accuracy
II predictions. by both PAMPA [139,140] and Caco-2 [235]. Dogs should not
be used for PPS III prediction of BCS III compounds due
12.2 BCS based strategy to the large difference of Ppara [160].
BCS has been introduced as a classification system for
biowaiver of a bioequivalent study in drug development. 13. Conclusion
However, BCS is also quite useful for navigating the strategy
in drug discovery. BCS has been used as a common language In this article, COAS is explicitly explained without leaving
among disciplines. any ‘black box’. Can simulation be as concrete as experiments
The BCS system can be used as guidance for reliability of in the future? As the quality and quantity of biological
oral absorption simulation. BCS categorises drugs into four information accumulate, the COAS will be more accurate.
classes based on the permeability and the dose:solubility The following items require further extensive investigation:
ratio. Basically, the rate limiting of oral absorption is reflected i) precipitation (COAS for BCS II dissociable compounds,
in these categories and BCS can be used as a guide of especially salts) (Section 7); ii) prediction for formulations
prediction reliability. such as SEDDS, solid dispersion, nano-particles and con-
trolled release (Section 10); iii) transporters and intestinal
BCS class I compound: high solubility/high
12.2.1 wall metabolism; iv) in silico prediction for solubility (crystal
permeability lattice energy) and permeability (transcellular and trans-
Predictability will be good (oral absorption simulation may porter); and v) GI physiology (including ethnic, age and
not be required for an immediate release formulation). disease difference). When used with an understanding of

Table 1. “Example” of Fa prediction confidence guideline.
BCS class API form/Permeation pathway Prediction process stepa
I II A II B III IV
BCS I ∆b-○ ○b ○b b b
BCS II Neutral ×b ∆ ○ ○
(dissolution limited) Free acid × ∆ ○ ○
Free base × ×-∆ ∆ ∆
Salts × × ×-∆ ∆ ○
BCS II Neutral × ○ ○ ○
(solubility limited) Free acid × ○ ○ ○
Free base × ×-∆ ×-∆ ∆ ○
Salts × × × ∆ ∆
BCS III Passive × ○ ○ ○
(permeability limited) Active × ∆ ∆ ∆ ○
BCS IV × × × ∆ ○
Special formulationsc × × × ∆ ○
a See text.
b ×: Poor predictability, ∆: Marginal predictability, ○: Reasonable predictability (e.g., with in 2 fold error with 70% probability), : Excellent predictability.
c SEDDS, solid dispersion, nano API particle, controlled release, etc.
its limitations, COAS will increase the efficiency of drug are: i) a large human physiology database (including ethnic,
discovery and development. age and disease differences) that enables virtual clinical
trial [236]; ii) the user consortium consisting of many phar-
14. Expert opinion maceutical companies that facilitate the knowledge exchange;
and iii) friendly graphical user interface. At present, various
14.1 A proposal for good simulation practice programs are commercially available, for example, SimCYP™,
When writing a report, model equations, physiological GastroPlus™, PK-Sim™ and IntelliPharm™.
parameters and drug parameters should be documented in An in-house program would be more suitable for drug
as much detail as possible to enable inspection by other discovery than drug development, as it allows high flexibility
scientists. When a commercial program is used, the user for the scientific investigation. High flexibility enables devel-
manual cannot be a reference for model equations and opment of tailor-made models for in-house experimental
physiological parameters unless it is accessible to all. Some tools, such as the artificial stomach duodenum system [111]
key experimental conditions of drug parameters, for and the dissolution–permeation systems [237,238]. Other
example, pH of Caco-2 assay, should also be described. As administration routes such as sublingual, intranasal, pulmo-
discussed in Section 12.1, predictability largely depends nary and opthomathology can be further incorporated. A
on the PPS. Therefore, in addition to parameters and new hypothesis on absorption mechanism and new drug
equations, PPS should also be clarified. When a parameter delivery mechanism may be added. Programming (coding)
fitting process is used in the prediction scheme, it should be resource is one of the reasons of prejudice against in-house
explicitly mentioned. development. Today, writing a program is not resource
Integrity of the PK data is important when the intensive. User-friendly programming media, such as Mat-
predictability is discussed with in vivo observed data. The Lab™, Mathematica™, Stella™, SAAM II™ and Excel VBA,
PK data analysis method should also be well documented. offer flexible programming capability. It is worth noting that
In addition, formulation (capsule, tablet, suspension etc), the best way to learn oral absorption simulation is to develop it.
solid form (free/salts, polymorph) and particle size should be
well documented. 14.3 Misconceptions in oral absorption simulation
The following sections list the misconceptions often encountered
14.2 Purchase commercial software or do it yourself? in drug discovery and development, in the literature and in
Commercial programs are more suitable for drug development some commercial COAS programs. The items with asterisks
than for drug discovery. The merits of commercial software are possible misconceptions if one uses the default functions

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and settings of certain commercial programs. The users of a > Peff of high lipophilicity compounds (logKoct,pH6.5 > 2)
commercial program should check it by themselves, rather can range 1 – 8 × 10-4 cm/sec depending on the bile
than completely trusting the program. micelle binding property [121]. This can result in eightfold
difference in Fa prediction.
14.3.1 Misconceptions about permeability
It seems that a simple linear regression between in vitro 14.3.2 Misconceptions about solubility and dissolution
permeability and Peff is often used for human Peff estimation Misconceptions about solubility and dissolution have been
and is provided as a default function in certain commercial summarised elsewhere [6]. In this section, additional miscon-
programs. However, this method is not appropriate for many ceptions are listed. The effect of bile micelles and the
cases, such as Ppara permeants, mUWL limited permeation solid surface solubility, which are important for the simula-
and transporter substrates. The possible misconceptions are tion of a low solubility compound and a dissociable
indicated as •, and the comments are indicated as >. compound (salts/free form), are often overlooked and
• FaSSIF solubility can be used with the free monomer appropriate function is not provided as default in certain
permeability in Caco-2.* commercial programs.
> Diffusion of bile micelle bound drug through the mUWL • Human FaSSIF solubility was used for rats and dogs.
and free (unbound) fraction at the epithelial membrane > Bile acid concentration in rats and dogs is higher than that
surface should be considered. in humans.
> Similarly, an apparent solubility from a solubility enhancing > When preclinical in vivo data are used to validate COAS,
formulation such as SEDDS cannot be directly used with appropriate solubility values should be used.
permeability of free (unbound) molecules. • The standard HH equation is used with FaSSIF solubility.*
• Peff values are the same among in vivo species because Fa > The micelle solubilisation should be taken into account.
is similar.* > If FaSSIF solubility (pH 6.5) and standard HH equation
> Rat Peff is ∼ 5- to 15-fold lower than human Peff due to the are used, the calculated solubility value in the stomach
difference of plicate and villi expansion ratio [165]. would be inappropriate.
> Peff in dogs may also be smaller than that in humans for • In the NBE, FaSSIF solubility was used with the free
transcellular and mUWL permeation [128,239]. monomer diffusion coefficient.*
> Peff in dogs may be larger than that in humans for > Diffusion of bile micelles is slower than that of
paracellular permeation [161]. monomer.
• Maximum Pep value is < ∼ 30 – 50 × 10-6 cm/sec, since the > If Dmono is used, the dissolution rate will be overestimated.
maximum permeability value in typical Caco-2 assay is in • Solid surface solubility and bulk fluid solubility are the same.*
this range. > Due to the self-buffering effect of dissolving drug, they are
> The mUWL of an in vitro assay can be ∼ 1500 – 3000 µm different in the case of dissociable compound and their
without vigorous stirring. This hinders the permeability. salts.
If the mUWL is removed, it could reach higher values > In certain commercial programs, the solid surface solubility
of > 1 cm/sec. cannot be reflected in the NBE (therefore, Ssurface is set equal
• Permeability does not depended on pH and pKa, because to Sdissolv). In this case, the difference of solid form
ionised percentage is almost 100% for many acids and bases (free/salts) cannot be appropriately captured.
in the pH range in the small intestine. • Salt formation does not increase the oral absorption because
> For passive transcellular permeation, the percentage of unionised the equilibrium solubility at a pH (in buffered media) is not
molecule is important (0.1 and 0.01% differs 10 times). changed by salt formation.*
• Permeability does not depended on pH and pKa, because > Dissolution rate can be increased by salt formation as
when unionised species is consumed for permeation, solubility at the solid surface is higher.
unionised species is generated from the ionised species as > After dissolving of salts, a super saturation state could
the equilibrium moves. be produced.
> Permeability is the speed of permeation, not the equilibrium value. > In certain commercial programs, supersaturation phenomena
The concentration can be interpreted as the pressure for speed. cannot be captured.
• The regional pH difference can be corrected by directly • Precipitation can be represented simply as first order decrease
applying pH partition theory to Peff values.* of concentration assuming no supersaturation.*
> The pH partition theory is only applicable for passive transcellular > It could be a good approximation if an appropriate precipitation
permeation, but not for mUWL and paracellular pathway constant is used.
permeation. > However, it should be noted that in the case of salt form
• In the case of solubility limited absorption, estimation of API (and formulations that could produce supersaturation),
Peff is not important. the nucleation process is required for precipitation of free
> Absorbed amount is permeability multiplied by solubility form and this is the origin of super saturation phenomena
(Equation 72). in the GI fluid.

• Relative velocity of a particle suspended in the fluid was > It seems that some validation studies mainly use BCS I
equal to the absolute fluid velocity.* and III compounds (and class II with high Fa) or PPS III
> A suspended particle flows with the bulk flow. (by using parameter fitting with in vivo data). In this case,
• No dissolution occurs when there is no agitation validation is limited to BCS I and III (passive permeation),
(the asymptotic diffusion term of 2 is ignored in the or PPS III.
Rantz–Marshall equation).* > Certain commercial programs lack several functions required
> Even in the absence of agitation, particles dissolve in for BCS II compounds (bile micelle partition, surface solubility,
the fluid due to the existence of concentration gradient nucleation, etc).
by space expansion around the particle (curvature effect) • Validation using in vitro and preclinical animal data is
(Section 6.3). meaningless, because the aim of COAS is to predict oral
• The intestinal fluid volume is 1.5 l in humans in the fasted state absorption in humans.
(GI tract is assumed to be 100% filled with the fluid).* > In a post Galileo’s era, a scientific theory has always been
> The small intestinal fluid volume in humans was suggested validated by simplified and well-controlled experiments [26].
to be ∼ 100 – 250 ml.
• Absorption from the colon is dominant for BCS class II and
III compounds.* Acknowledgement
> Due to the long residence time in the colon, extensive colonic
absorption is often predicted. However, small surface area, The author would like to thank M Cram (Pfizer, PGRD,
thick mucus layer, viscous and solidified cymes (faeces), low bile UK)for his critical reading of the manuscript and the Pfizer
concentration, etc., all negatively affect the colonic absorption. global formulation biomodelling network members, espe-
cially, S Sutton, K Sagawa, M Gumkowski, P-C Chiang, J
14.3.3 Other misconceptions Ma, and drug delivery group members, especially, M
• In silico prediction of feeding parameters (e.g., Sdissolv) from McAllister, J Bennett, L Reading and U Vivanco. The author
chemical structure is accurate. Experimental measurement would like to thank H Jones and J Davis (Pfizer, PGRD,
is no longer required.* UK) for discussions and B Henry and T Mano (Pfizer) for
> Even for Koct,0, in silico prediction has a significant error in their support in this investigation.
real drug discovery [240] and Koct,0 is routinely measured
when compound is available [167]. Declaration of interest
• Commercial COAS program is perfected and fully validated
for all cases.* The author is an employee of Pfizer: he states no conflict
> The predictability of COAS depends on the chemical of interest and has received no payment in preparation of
structure, API form and formulation. this manuscript.

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Appendix 1. Acronyms. Appendix 1. Acronyms (continued).
API Active pharmaceutical ingredient Do Dose number

Dose Dose amount (= ∑ij XAPI,ij,t=0 )
BCS Biopharmaceutical classification
system dXabs/dt Absorption rate
CNT Classical nucleation theory Fa Fraction of a dose absorbed
Fd Dissolved fraction
COAS Computational oral absorption
simulation hHJ Criteria value for Hintz Johnson
model
FaSSIF Fasted stated simulated intestinal
fluid hpUWL Unstirred water layer thickness of
particle
FeSSIF Fed stated simulated intestinal fluid
hWF Criteria value for Wang Flanagan
GI Gastrointestinal model
Jmax Maximum flux
mUWL Unstirred water layer of intestinal
membrane Jnc Primary nucleation rate per volume
per time
NBE Nernst Brunner equation
kabs Absorption rate constant
PAMPA Parallel artificial membrane
permeation assay Ka Dissociation constant
PC Phosphatidylcholine kB Boltzmann constant
PK Pharmacokinetics Kbm Bile micelles water partition

coefficient
PPS Prediction process step
Km Michaelis-Menten constant
pUWL Unstirred water layer
of particle Koct,0 Octanol water partition coefficient
SEDDS Self emulsifying drug Koct,pH Octanol water distribution

delivery system coefficient at a pH
TC Taurocholic acid Ksp Solubility product
General parameters Kt,k First order transition kinetic

constant
C Concentration
LGI Length of GI tract
D Diffusion coefficient
lp Representative length of particle
N Number of particles
matom Number of atoms in molecule
P Permeability
mp Melting point
S Solubility
X Drug amount (mole or weight) NA Avogadro number
f Fraction of drug molecules NAPI,GI,k Number of API particle bins in GI

position k
Individual parameters
Pactive Active transcellular permeability
Acc Accessibility to villi surface
PE Plicate expansion
An Absorption number
Peff Effective intestinal membrane
Cactive Effective concentration for active permeability
transport Pep Epithelial membrane permeability
Cbile Concentration of bile acid Ppara Paracellular pathway permeability

Pplicate Plicate surface permeability
Cdissolv,ss Steady state concentration
PSF Particle shape factor
Cwater Concentration of water
Ptrans Passive transcellular pathway
DF Degree of flatness of intestinal tube permeability
Disp Dispersion coefficient for GI transit PUWL mUWL permeability
Dn Dissolution number PWC Permeability by water conveyance

Appendix 1. Acronyms (continued). Appendix 1. Acronyms (continued).

Rep Reynolds number of particle Zch Zel’dovich number
RGI Intestinal tube radius Zpara Coefficient representing
rmono Molecular radius paracellular pathway charge
rp Particle radius β Lump constant of foreign particle

number, sticking provability, etc
Rpara Apparent pore radius of the
paracellular pathway γ Surface energy
SAGI GI surface area for absorption ∆Gnc Energy barrier for nucleation
SAAPI Particle surface area of API ∆t Integration interval

Sc Schmitt number λnc Interfacial attachment resistance (in

length dimension)
Shp Sherwood number of particle
ν Kinematic viscosity
Ssurface Solubility at solid surface
ρ True density of a drug
vatom Relative volume of atom
ψnc Interfacial reaction rate correction
Vc Velocity of intestinal fluid factor
VGI GI fluid volume Subscripts
vm Molecular volume +,-,++… Dissociated molecules (representing
Vme Velocity representing microeddy its charge number)
effect 0 Undissociated molecules
Vrel Relative velocity between fluid and API API particle
particle
NFP Newly formed particle by

Vt Terminal (sedimentation) slip precipitation
velocity
z Molecular charge UWL Unstirred water layer
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Afﬁliation
Kiyohiko Sugano
Pfizer - Research Formulation
Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
Tel: +44 (0) 1304 644338;
E-mail: Kiyohiko.Sugano@pfizer.com

Sugano 2009

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Review

8. Permeation: absorption into

10.1517/17425250902835506 © 2009 Informa UK Ltd ISSN 1742-5255 259

Dissolution Dissolved drug Permeation Absorbed drug

Figure 1. Schematic presentation of oral absorption from a dosage.

260 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

Changes with time Differential equation

Chemical structure/physicochemical property rp,API Eq. 30 Integration

Lipophilicity Dissolution/particle growth

hpUWL()NFP SANFP XNFP

Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

PSF (NFP) r (NFP)

Eq. 67 P Eq. 59 P Eq. 55 PUWL

Figure 2. Overview flowchart of computational oral absorption simulation.

262 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

Unstirred water layer

Epithelial cells at villi top

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 263

Standard HH equation relationship between the physicochemical properties and the

1 where Koct,0 is the octanol water partition coefficient

and bile micelle partition are related to lipophilicity expressed

Both positively and negatively charged drug molecules

264 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

adjacent to the solid surface. In most cases, rapid equilib-

700 where XAPI,ij is the amount of drug (weight or mol) in a

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 265

WF models, respectively) [82,83] for spherical particles.

is determined by Ksp [74]), resulting in faster dissolution. In = +

266 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

A. Dosed as free base

Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

Figure 6. Dissolution of a salt and precipitation of a free form in a buffered medium.

268 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

When spherical shape is assumed, the number of particles (34)

where vm is the molecular volume, matom is the number of

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 269

At present, there are many unknown factors for nucleation. (39)

precipitation, depends on the free energy barrier for formation

270 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

Monomer Dimer Trimer i-mer 8. Permeation: absorption into body

In this section, a theoretical scheme to represent the intestinal

discussed in Section 8.6 and 8.7, respectively.

7.3 Acquisition of drug parameters = X dissolv + X others

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 271

0.07 cm (0.7 mm)

pKa Ppara Ptrans Pactive

0.0018 cm (18 µm)

Figure 8. Morphology of human small intestinal and permeation pathways

volume of distribution (Vd) in pharmacokinetics (kel = CL/Vd). (49)

dX abs For cylindrical tube, DF = 1 and SAGI/VGI is:

272 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

The plicate permeability is the tandem process of mUWL

expansion. Because mUWL and epithelial membrane per- particles [114].

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 273

274 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 275

(68) In this section, advanced applications of COAS are discussed.

(69) 10.2 SEDDS

276 Expert Opin. Drug Metab. Toxicol. (2009) 5(3)

80 also decrease the diffusion coefficient and free fraction,

Quantitative simulation of biological processes in the intestine

Expert Opin. Drug Metab. Toxicol. (2009) 5(3) 277

is usually limited [208,224], Tsi can be set to the small intestine