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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5571_Библиотеки_им_академика_М_И_Перельмана
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discussed here and physical form stability in Section 3.5. For an oral drug to have good
bioavailability it needs to be stable in vivo and in its formulation so that the
performance is consistent over the desired dosing interval. For drugs that are ionizable
or contain pH-sensitive functional groups, it is important to measure the pH-stability
profile so that the impact of stability on absorption and formulation development can
be assessed. The major chemical reactions that lead to degradation of the drug in the
GI include hydrolysis, oxidations, and reductions [17, 29]. These processes are often
catalyzed by pH, and/or enzymes in the small intestine, and the bacterial flora of the
lower intestinal tract. Stewart and Tucker have listed some common classes of drugs
that are subject to hydrolysis. The list includes esters, thiol esters, amides, sulfonamides, imide s, lactams, lactones, and halogenated aliphatics [18, 30–32]. Intestinal
(including colonic) stability is an important factor to consider for compounds that
need controlled release profiles. Some examples of drugs that are biotransformed in
the large intestin e include atropine, digoxin, indomethacin, phenacetin, and sulfinpyrazone [18, 33].
Stability assessment in common cosolvents is an important consideration because
solubilizing agents are often used to increase solubility in formulations. This is
especially true for poorly soluble compounds, where high percent ages of organics are
used. Other types of stability such as photo, hygroscopicity, and heat sensitivity need
to be monitored as well. These can play an important role on the final product
development (dosage form), shelf life, and packaging.
3.4. DISSOLUTION AND SOLUBILITY
3.4.1. Dissolution Rate, Particle Size, and Solubility
For oral drug delivery,the availability of a drug to be absorbed depends on its ability to
dissolve in GI fluids during the transit time through areas of the GI track where it can
be absorbed. If the rate of dissolution (not to be confused with its equilibrium
solubility) is the rate-limiting step in drug absorption, any feature affecting the
dissolution rate will have an impact on bioavailability. The dissolution rate can be
expressed by the well-known diffusion-layer model, modified Noyes–Whitney
equation [34–37]:
dc
dt
¼
DA
hn
ðC
s
CÞ
where the dissolution rate is given by dc/dt, D is the diffusion coefficient, h is the
diffusion layer thickness, A is the surface area of drug exposed to the dissolution
media, v is the volume of the dissolution media, C
s
is the saturated solubility of the
drug in the dissolution medium at the experimental temperature, and C is the
concentration of drug in solution at time t.
A common practice to increase the apparent dissolution rate and subsequently the
bioavailability for compounds, where the oral absorption is limited, is to decrease the
128 ABSORPTION AND PHYSICOCHEMICAL PROPERTIES OF THE NCE
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particle size of the drug. Reducing the particle size increases the surface area available
to the dissolution media and increases the overall apparent dissolution rate. The use of
nanoparticles for the delivery of poorly water-soluble drugs has been increasingly
used [36, 38–46] . In addition to dissolution improvements, nanolized particles offer
advantages such as GI retention [51], and solubility improvements. There are various
patents and publications describing nanoparticulate drug preparations and applications [47–57].
Particle size reduction is accomplished by two general approaches. These are (1)
dissolving the drug and reconstructing particles from their molecular state, such as
fast precipitation or rapid expansion; or (2) by breaking large particles, such as by
milling. The approach of producing and maintaining a stable particle size reduced
system is not free of problems. Challenges such as solid form changes, physicochemical stability, and well-characterized formulations must be addressed. Furthermore, if a wet milling/suspension system is used, the effect on changing particle size
in an aqueous environment needs to be understood. The potential for particle
agglomeration has been examined by researchers and summarized in detail [36,
47, 48]. In theory, the new surface area generated by either approach requires an
energy cost. The energy increas e due to the increase in surface area by either
procedure will create a less stable system. Such a system will have a tendency to
offset the increase in surface area and thereby reduce energy by agglomeration. This
phenomenon can be controlled by introdu cing surfactants and controlling temperature. The addition of surfactants can provide stabilization at longer times due to an
increased energy barrier and, along with lowering temperature, prevents particles
from coming close enough to cause agglomeration [36, 48].
Despite the advantages of increasing the dissolution rate through particle size
reduction, the solubility of the drug plays the most pivotal role in the absorption
process. Solubility is one of the most important properties impacting bioavailability
because of its role in dissolution and absorption. Solubility and permeability are the
two main factors defining the biopharmaceutics classification system (BCS) used by
the FDA as a guide for predicting intestinal drug absorption (Figure 3.1) [58].
Although some materials such as glucose and
L-amino acids are absorbed by active
transport across the intestinal barrier, absorption by passive diffusion is far more
common [59]. For a drug administrated orally to enter the circulation system, it must
dissolve in the solution phase first and then diffuse into and across the wall of the
intestinal lumen. Improving the solubility of the drug is a major approach to
absorption enhancement for oral drug delivery. In preclinical and clinical development, various methods and vehicles are used to enhance the solubility of drug
candidates. Vehicles such as cosolvents, emulsions, and cyclodextrins are commonly
used to improve drug solubility. Despite the success of using these tools, a solid
understanding of factors affecting solubility is crucial in addressing deficiencies in
formulation caused by poor solubility.
Solubility of a given compound in aqueous media is governed by the intermolecular forces between the solvent and the solute and the entropy changes associated
with that interaction. A full treatment of solubility as applied to pharmaceutics is well
beyond this text [60–62]. However, it should be understood that factor s such as
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temperature (Van’t Hoff equation), pressure, pH (Section 3.4.2), the ionic strength of
the aqueous media, and the solid form (Section 3.5) used will affect the balance of
these interactions and change the overall solubility.
Increasing solubility and supersaturationin GI fluid are important attributes that can
affect drug absorption. Supersaturation is particularly important for compounds with
poorintrinsicsolubilityand is thelimitingfactor for absorption.Creatingormaintaining
supersaturation in the GI fluid is a must to enhance absorption of these compounds.
Formulations with cosolvents, the use of excipients for solubilization, inclusion, or
suspension, and the use of pH adjustment or salts have been used for this purpose.
3.4.2. pH and Salts
In practical terms, the medicinal chemist is often asked to find efficacious candidates
within a series that have better solubility and in many cases pharmaceutical scientists
are required to formulate low solubility materials to properly assess efficacy and
toxicity during exposure. Adding ionizable groups that have a pK
a
in a physiologically
useful range can provide options for formulators and materials scientists to solve
solubility and dissolution rate issues [64]. For ionizable drugs, the intrinsic solubility
is defined by the union ized form. However, the solubility profile will be pH sensitive
and optimizing solubility in the formulation may be achieved by altering the pH of the
solution/suspension or by dosing a soluble salt.
The solubility of an ionizable compound can be calculated from its pH-solubility
profile as given by the Henderson–Hasselbalch equation. For example, for a slightly
soluble weak acidic electrolyte with single pK
a
, the solubility and pH can be expressed
as follows:
HA
ðsolidÞ
! HA
ðsolÞ
HA
ðsolidÞ
! Aþ H
þ
Class 4 LS/LP
Low solubility
Low permeability
Class 3 HS/LP
High solubility
Low permeability
Class 2 LS/HP
Low solubility
High permeability
Class 1 HS/HP
High solubility
High permeability
High Low
Permeability
High
Low
Solubility
Figure 3.1 Biopharmaceutics classification system.
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ABSORPTION AND PHYSICOCHEMICAL PROPERTIES OF THE NCE
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Ka¼
½A½Hþ
½HA
ðsolÞ
pKa¼ log
½A½Hþ
½HA
ðsolÞ
¼ log Hþ½þlog
½A
½HA
ðsolÞ
pH ¼ pKaþ log
½A
½HA
ðsolÞ
ðHenderson-- Hasselbalch equationÞ
Sol
ðtotalÞ
¼½HA
ðsolÞ
þ½A; where ½HA
ðsolÞ
¼ intrinsic solubility ¼ S
0
Sol
ðtotalÞ
¼ S01 þ
K
a
½Hþ
Sol
ðtotalÞ
¼ S01 þ 10
pH pK
a
ðÞ
ðAcidÞ
¼ S01 þ 10
pKa pHðÞ
ðBaseÞ
¼ S01 þ 10
pKa pHðÞ
þ 10
pH pK
a
ðÞ
ðAmpholyteÞ
For a simple acid base titration, the above relationship holds only at equilibrium,
where the product of the ionized species and counter ion is below its solubility product
(K
sp
). The Kspof a salt is defined as the equilibrium constant for the aqueous
disassociation into its ionic species as in the example below:
A
x
B
yðSÞ
¼ xA
y þ
ðaqÞ
þ yB
x
ðaqÞ
Ksp¼ A
y þ
½xB
x
½
y
This equilibrium region is typically referred to as pH < pH
max,
where pH
max
is defined
as the pH where the solution is saturated with respect to both the free and salt forms.
Once the pH drops below pH
max
and the salt forms, the solubility is governed by the
K
sp
[63–65]. This phenomenon is illustrated in Figure 3.2. The quadratic equation for
expressing the pH
max
of a base is
pH
max
¼ pKaþ log
S
0
ffiffiffiffiffiffiffi
K
sp
p
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However, enhanced salt solubility may not guarantee better in vivo absorption
[66–68]. When a salt or pH-adjusted formulation is used, the degree of bioavailability
improvement may be largely dependent on the degree of supersaturation with respect
to the equilibrium solubility in GI tract [69, 70]. The effect of better solubility on
bioavailability may be neutralized in the gastric or intestin al environment when
changes in the pH decrease the solubility and cause the ionized species to precipitate
as the free form. Table 3.1 lists reported pH changes during transit in the GI tract of a
fasted and fed human [71, 72]:
For a weak base, when the pH rises above the pK
a
, the degree of supersaturation
becomes a kinetically controlled phenomenon and the improvement in bioavailability
due to supersaturation is dependent on the rate of free form precipitation. Regardless
of the pH of the system, the pH change induced by the salt at the dissolution layer may
facilitate dissolution and retard free form precipitation. The salt acts as its own buffer
once in the solvated state and the dynamics of precipitation and absorption may result
in a net enhancement of amount dissolved and absorbed. The kinetic nature of the
process often leads to higher exposure variability in vivo. The inclusion, if feasible, of
pH solubility, pH
max,
and Salt versus Free base region
1.0
10.0
100.0
1000.0
10000.0
100000.0
1000000.0
876543210
pH
Solubility uM
pH solubility
pH
max
of a salt
Region II Solid Phase:
Salt
BH
+A-
(solid)
BH++A
-
Region I Solid Phase:
Free base
B
(solid)
B + H++ A
-
Figure 3.2 pH solubility curve for a basic drug.
TABLE 3.1 Gastrointestinal pHs for Human Subjects
Site pH Fasted pH Fed
Stomach 1.4–2.1 3.0–7.0
Jejunum 4.4–6.6 5.2–6.2
Ileum 6.8–8.0 6.8–8.0
Colon 5.0–8.0 5.0–8.0
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ABSORPTION AND PHYSICOCHEMICAL PROPERTIES OF THE NCE
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basic or acidic functional groups in drug candidates with pKa’s where the molecule
will be fully ionized within the desired physiologic relevant pH range will mitigate
this issue.
The selection of a suitable counter ion can be important for a salt approach [69, 70].
Supersaturation and precipitation phenomenon can be expressed as the change in
Gibbs free energy for transitioning from a supersaturated solution to equilibrium:
DG ¼R
g
T ln S
x
where Rgis the gas constant, T is the absolute temperature, and Sxis the supersaturation ratio which is concentration dependent. As the change in free energy
increases, the driving force for precipitation increases. Thus, the salt with the highest
solubility may quickly precipitate and may not necessarily provide the highest in vivo
exposure.
Classically for many drugs hydrochlorides were often the first and sometimes the
only salts considered when searching for a more soluble form. However, the presence
of chloride ions in gastric acid may well depress solubility in vivo compared to other
salt forms because of common ion effects [73–76]. It is a particular concern in the
stomach, where the acidic pH and high concentration of the chloride ion can be
problematic for many basic compounds. Conversion in the stomach to a hydrochloride salt is a problem if the hydrochloride salt is poorly soluble or oppositely if the
hydrochloride salt is highly soluble in the stomach but precipitates in the small
intestine due to unwanted physicochemical changes (i.e., a salt or particle size
change). The conversion to a hydrochloride salt can be avoided by use of enteric
coating techniques [18, 77].
In the intestine, the presence of bile salts and other components such as lipids
usually improve the intrinsic solubility of the free base and shift pH
max
to higher
values [18]. The potential for absorption enhancement by salts are typically explored
via in vivo studies in small animals prior to administration to humans. Animal studies
provide useful rank ordering for different salts, but are not necessarily linearly
predictive of human absorption. Caution should be taken that these preclinical
formulations should contain excipients compatible with human administration and
it should be understood that they may not encompass all possible human physiological
conditions [70].
3.4.3. In Vivo Solubilization
Drug solubility can be enhanced by food and natural bile production in the stomach
and intestine. Components such as bile salts, lecithin, and monooleins help solubilize
drugs. However, depending on the physicochemical properties of the drug, the degree
of solubilization may vary. Log P, MW, and specific interactions between drugs and
bile salts have different degrees of impact on bile–lecithin micelle solubility [78, 79].
There is growing evidence that bile salt–lecithin mixed micelles are good solvents for
lipophilic drugs [79–81]. For drugs that fall into this category, the total solubility of
the drug is proportional to the bile salt concentration and there is an increase in
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solubilization with an increase in log P [78, 82–85]. Thus, for drugs that are lipophilic,
solubility measurements in physiologically relevant media are highly recommended.
Two physiologically relevant media developed by Dressman et al. based
on literature and experimental data in dogs and humans have been used extensively
in the pharmaceutical industry and academic research. They are the fasted-state
simulated intestinal fluid (FaSSIF) and fed-state simulated intestinal fluid
(FeSSIF) [86, 87]. The compositions of FaSSIF and FeSSIF are listed in Table 3.2.
3.5. SOLID STATE
The three classical states of matter are solids, liquids, and gases. The most common
physical state targeted for storage and formulation of an active pharmaceutical
ingredient (API) is a solid because of its relative stability and reproducibility. Even
in the case of liquid formulations, the API is typically harvested as a solid and later
incorporated with solvents and excipients. An API may precipitate in a number of
different solid-state forms. These are commonly classified as amorphous, partially
crystalline (crystalline with some degree of disorder), and crystalline. Crystalline
materials can further be classified into their polymorphic forms or in the case of
solvent inclusion, solvates (desolvated or partially desolvated solvates).
Amorphous materials such as plastics or glasses are solids that are made up of a
random arrangement of their constituent parts (atoms or molecules). Figure 3.3 shows
a representation of amorphous and crystalline solids. The purely amorphous form is
the highest energy (DG) solid form available and is thermodynamically unstable with
respect to its crystalline counterparts. As a result, if a nucleus of crystalline material
was to form and there was enough motility in the system to allow the molecules to
rearrange, the amorphous material will change form and crystallize. Materials that
become kinetically ‘‘stuck’’ between crystalline and amorphous phases are referred to
as partially amorphous, partially crystalline, or crystalline with disorder. This can
include mesophases with liquid crystalline behavior [88]. There may be an infinite
number of different amorphous and partially crystalline states depending on the
TABLE 3.2 Composition of Two Simulated Intestinal Fluid Media Used
for In Vitro Testing of Drug Solubility
FaSSIF
a
FeSSIF
b
Sodium taurocholate 3 mM Sodium taurocholate 15 mM
Lecithin 0.75 mM Lecithin 3.75 mM
NaOH (pellets) 0.174 g NaOH (pellets) 4.04 g
NaH
2PO4.H2
O 1.977 g Glacial acetic acid 8.65 g
NaCl 3.093 g NaCl 11.874 g
Purified water qs. 500 mL Purified water qs. 1000 mL
a
FaSSIF media has a pH of 6.50 and an osmolality of about 270 mOsmol/kg.
b
FeSSIF media has a pH of 5.00 and an osmolality of about 670 mOsmol/kg.
134 ABSORPTION AND PHYSICOCHEMICAL PROPERTIES OF THE NCE
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orientation of the molecules in the amorphous material and the degree of crystallinity
that is incorporated.
Crystalline materials are well-ordered solids, whose constituent parts are arranged
to produce a repeating pattern throughout the solid lattice. The minimum arrangement
of parts (molecules) that can be translated throughout the solid is defined as the unit
cell. It serves as a building block for the solid and is unique to the molecule in that
particular molecular arrangement. However, for a given system, a molecule may
crystallize into more than one type of unit cell. These different configurations are
defined as polymorphic forms and have different physical properties such as melting
points and solubility [89, 90]. Also, there may exist related forms such as hydrates
(water) or other solvates, where a solvent molecule is incorporated into the lattice to
produce a new form. The most common analytical tool used to identify the form of a
drug candidate is powder x-ray diffraction. Figure 3.4 shows powder x-ray diffraction
data for an amorphous form, a hydrate, and two polymorphic forms of the same
candidate.
Ostwald’s rule of stages and Gay-Lussac’s observations predict that the progression of discovered forms for a particular molecule over time will be from the highest
energy form to the lowest [91]. For the medicinal chemist this often means that an
amorphous form is first isolated by quick stripping of the solvent or by lyophilization
and then a more stable crystalline form will appear as conditions allow. The most
stable form at room temperature will eventually be discovered and the system will be
at equilibrium (assuming no solvates). However, in reality this is not necessarily true.
The likelihood for crystallization to occur within a given system is completely
dependent on the formation of a stable nucleus of a crystalline form and the ability of
that nucleus to grow. Given that the most stable form at a particular temperature is
thermodynamically favored in any solvent except when a solvate of that solvent
that affect the rate of polymorphic or solvate transformation can include solvent
solubility, impurities that impact nucleation or growth, the energy difference between
the two states, and the temperature of the entire system [92–94].
Another important concept is the relationship of polymorphs with respect to
temperature at a given pressure. Figure 3.5 shows a general example of the differences
Figure 3.3 A simple two-dimensional example representing a crystalline to amorphous
system.
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in energy for two types of polymorphic systems with respect to temperature. In each
graph, the Gibbs free energy curve for Forms 1 (dashed line) and 2 (solid line) are
shown as a function of temperature. The melting points (T
m1
and Tm2) are defined by
intersection of the liquidus line (above which the material would be a liquid) with the
energy curve for the specific form. T
c
is the crossover temperature between Forms 1
and 2.
The energy temperature diagram on the left depicts a monotropic system where
Form 1 is metastable (higher energy) with respect to Form 2 at all temperatures below
Figure 3.4 Powder X-ray diffraction data showing different forms of the same molecule.
Figure 3.5 Energy diagrams showing an example of the thermodynamic relationships
between two polymorphs.
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ABSORPTION AND PHYSICOCHEMICAL PROPERTIES OF THE NCE
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its melt. The diagram on the right shows an example of an enantiotropic system where
there is a crossover at some temperature (T
c
) prior to the melting onset. For the
enantiotropic system, Form 1 becomes more stable (lower energy) above the
crossover temperat ure. Thermodynamically, crystallizations will favor the most
stable form at the temperature of the crystallization. However, kinetic conditions
and the effect of the microenvironment may cause the nucleation and growth of the
unstable form.
For either system if the metastable form is harvested, it may or may not be
physically stable depending on the appropriate conditions for the nucleation and
growth of the more stable form. Solids may spontaneously undergo a solid- to-solid
form conversion without the presence of solvent mediation. However, in most cases
the more stable form can be achieved by recrystallization (at a temperature below T
c
for the enantiotropic system) with seeding of the stable form or by slurry in a solvent
that provides enough solubility to allow for the transfer of material from one form to
another. If these techniques are not successful, it is often the role of impurities that
may act as nucleation or growth inhibitors [94].
A good method to determine the unknown stable form at a given temperature is to
slurry clean material in a panel of solvents of good solubility. Anecdotal evidence
suggests that for reasonable slurry times (1–2 weeks) a solubility of 8 mmol or
higher should be targeted [94]. In practice, a number of solvents with varying
chemical properties should be used in stable form screening to provide the best
chance for solubiliz ation of the API and to minimize/change impurity profiles.
Why do crystallinity, polymorphism, or solvates matter to a discussion of ADME
properties? The physical form of a material affects a multitude of physical properties
that can impact the bioavailability and development of a drug candidate [89, 95].
Some examples of these include:
.
solubility and dissolution rate;
.
physical and chemical stability;
.
melting point, hygroscopicity, and solvent retention;
.
particle size, morphology, hardness, and bulk density;
.
purity.
A change in the form of a substance will affect the physical properties. However,
the impact of the form on solubility and dissolution rate is the most important
consideration for patient safety. If a drug candidate’s exposure is dissolution ratelimited (i.e., permeability is high enough that a change in solubility will impact the
amount of API being absorbed and the clearance is low enough that the drug becomes
systemic), any change that results in the crystallization of a more stable form will
cause a loss of exposure and the possibility that the drug may become subtherapeutic.
Alternatively, if a higher energy form is used, exposures may become greater due to
higher absorption, and toxicity may occur. This may have a deleterious affect on a
project at any stage and is the reason that control of the physical form or proof of
bioequivalence is required by the FDA [96].
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