USING THE POLARITY CHARACTERISTICS OF A DRUG’S FUNCTIONAL
GROUPS TO ESTIMATE SOLUBILITY CHARACTERISTICS
Lesson Objectives
1.
2.
3.
4.
5.
6.
Understand what is meant by logP; know the difference between MlogP
and ClogP
Utilize the polarity of a drug molecules functional groups to estimate the
water solubility and permeability capacity of that drug molecule
Know the general limits to logP for ability to cross lipid membranes
(transition through various biological compartments such as gut and
vasculature)
Know the general limits to logP for ability to show sufficient solubility in
water
Know how the limits to membrane permeability can be used to
therapeutic advantage, as in the case of Mannitol and Sorbitol
Understand how different solubilities are required for different
circumstances, as with the formation of prodrug esters of
Chloramphenicol with carboxylic acids of differing lipophilicities
Lemke Method
Organic Functional Groups, Introduction to Medicinal Organic Chemistry, 4th
Ed., T.L. Lemke; Lippencott, Williams & Wilkens (2003)
Foye’s Principals of Medicinal Chemistry, 5th Ed., D.A. Williams & T.L. Lemke;
Lippencott, Williams & Wilkens (2003)
a.
Focuses on those functionalities that can contribute to increased
aqueous solubility and assigns a “carbon carry along value”
i.
b.
This is to say Lemke’s view focuses on solubility decreasing with
increased molecular size and assesses functional group content to
determine whether the influence of increased size (increased Van
der Waals forces, decreased entropy of water) has been offset
Ionization (full dissociation: strong acid with strong or weak base, strong
base with strong or weak acid) contributes a whopping 20-30 carbon to
the estimation
i.
Large variation in the number of “carbon’s carried” shows the
difficulty of both approaches when accurately determining ionization
influence
2. logP
a. Also sums functional groups, but includes values for both lipophilic
and hydrophilic functionalities
b. Greater the number, the lower the solubility, since P
octanol/water partition ratio; i.e. the amount of drug molecule that
dissolves in octanol divided by the amount that can be dissolved
in water
c. USP defines solubility as > 3.3%, or ≈ logP ≤ +.5
Aside for the values listed for the nitro groups, the p values in the table above
weigh the values for various systems (such as aliphatic vs. aromatic). This
makes the approximation rather crude as the ability for charge to disperse is
very system dependant.
Notice the large positive value for intramolecular hydrogen bonding, IMHB =
.65, which reflects the importance of hydrogen bonding to water for
solubilization.
Interpretation of logP Values – Limits to Solubility Characteristics
Biological membranes behave as if lipids (polar heads being solvated)
As such, biological membranes act as barriers to highly polar species (a
fully ionic species being the upper limit to polarity with regard to
individual functional groups)
In order for a drug to absorb by the oral route, it must have sufficient
hydrophilic character to dissolve sparingly (again note these are
equilibrium processes).
In order for a drug to absorb by the oral route, it must have sufficient
lipophilic character to cross biological membranes
If drug absorption is a balance of lipid and water solubility, let’s ask the
boundary questions
How much water solubility is too much?
How much lipid solubility is too much?
Perusing lists of physicochemical properties for therapeutic agents, we find
(tossing out values that are likely to be carrier mediated) typical logP values do
not exceed -4.
Some examples are Mannitol (-4.67), Sorbitol (-4.67), Zanamivir (3.75), and Tobramycin (-3.44)
o
Mannitol does not cross the blood brain barrier – in fact, it does
not cross any barrier and must be administered IV. It is,
however, freely filtered by the kidney; this fact coupled to its high
osmotic tendency makes Mannitol a useful osmotic diuretic
o
Sorbitol is administered orally, but for use as a laxative (bear in
mind it is used as a sweetener in some “sugarless” candies)
o
For Tobramycin the story is the same, IV route or available by
inhalation for CF patients with Pneumonia (the primary use for
this aminoglycoside antibiotic)
Tobramycin is not absorbed orally
Considering the structural similarity between the
aminoglycosides (e.g.’s Gentamicin, Kanamycin) would
you expect any of these compounds to be available
orally?
Notice that Tobramycin is ionizable, but that only
makes the compound more polar – we are considering the
polarity of unionized species to see if they (1) are water
soluble (2) have the potential for crossing biological
membranes
o
Zanamivir (Relenza) is available by inhalation for influenza A &
B
Oral bioavailability = 1-5%
What is a potential plus of this limited ability to cross membranes?
(Hint: Tobramycin is at times administered intrathecally or intraventricularly for
CNS infections)
Well, let’s try something in the logP = -2 to -1 range
Ganciclovir (-2.07)
o
Available orally for CMV infection but is poorly bioavailable
o
Bioavailability: 5% fasting, 6-9% with meal, 22% with high fat
meal
o
Nucleoside analog apparently accounts for high presence in
CSF, ca. 40% of plasma levels
Oxytetracycline (-1.22)
o
o
Good oral availability
Tetracyclines still have widespread use, though there are
many resistant microbes out there
Ceftriaxone (-1.76)
o
3rd generation cephalosporin
o
Not absorbed orally, used for serious gram neg. infections
o
Does penetrate into CSF (useful for meningitis) and crosses
the placenta
Ceftibuten (-1.06)
o
o
Also third generation cephalosporin, with similar profile to
ceftriaxone
Rapidly absorbed as capsule or oral suspension
As may be seen by comparing Ceftrioxone to Gancyclovir, the correlation of
logP to oral bioavailability is only an approximation. To emphasize this point, 2
other members of this class are Cefotaxime (-.31) which is not absorbed orally
and only available as an IV injection, and Cefixime (-.51) which is available
orally, though absorption is slow and incomplete.
On the other end of the spectrum we must ask the question how much
lipophilicity is too much
The major concern for oral absorption is dissolution, since undissolved
drug molecules are not absorbed
We do have some control over water solubility in most cases (ca. 90% of drugs
have an ionizable functionality), since we have the capacity to form ionized
molecules or salts which vastly improve the ability to interact with water in a
most favorable fashion. Further, the GI tract varies in pH from 1 – 8, and so
drugs will optimally dissolve according to their pH.
Note that the logP of Phenobarbital is 1.71
Notice also the y-axis is mg/100min/cm2. This is to say that surface
area of the solid drug surface is important for dissolution.
If we consider the above in terms of absorption of a drug, ultimately
into the blood stream, we should be able to see from the above that we
are balancing dissolution and solubility with membrane permeability for
solid oral dosing. From a biopharmaceutics standpoint the biological
absorbing surface is also crucial, so the upper small intestine ends up
absorbing a large amount of drug agents.
Again, tossing out compounds that are likely to be carrier mediated (by
approximation to endogenous compounds) we find therapeutic agents generally
fall below 9
2 examples are Amiodarone (8.59) and Halofantrine (8.86)
Amiodarone (8.59)
o
Antiarrhythmic used for life threatening ventricular arrhythmias
o
Slow and incomplete bioavailability from oral dosing (generally
ca. 50%)
o
o
o
o
Peak plasma in 3-7 hrs
Steady state plasma levels not reached until 1-5 months of daily
therapy
Onset of action 2-3 months
Huge volume of distribution 70 L/kg, Huge elimination half-life
with persistence of side effects
Halofantrine (8.86)
o
o
o
Synthetic antimalarial related to mefloquine and quinine
Absorption is poor and widely varied on an empty stomach but
is increased ca. 10x with a high fat meal
Why?
It should be noted that with the above examples that increased bioavailability
with food are contrary to the usual case of decreased absorption (lower AUC) or
decreased Cp max
Let’s look at a few compounds that have more usual values (notice that the
barbituric acid core structure helps to control for some of the anomalous
differences that might be experienced when comparing highly varied structures
of differing logP values)
Again, aside from erratic absorption with high logP compounds, they also tend
to sequester into fatty tissues, thus resulting in very high volumes of distribution
and long half lives. Just so you know (believe me, you will commit this
relationship to memory eventually…but not for this test)
t1/2 = (.7 x VD)/Cl, where the systemic clearance, Cl, is the fraction of the
distribution volume cleared of drug per unit time (for drugs which are cleared by
metabolism in the liver, the clearance cannot exceed the hepatic blood flow of
1.25L/min)
The following table and graph provides evidence for absorption following logP
across a series of compounds (with similar pKa’s)
Note the above is for chloroform/water as the partitioning system. The values
for octanol/water logP are
Secobarbital 2.33
Phenobarbital 1.71
The relative ranking is the same
The above correlation should help drive home the idea that drug absorption is a
balancing act between aqueous solubility and membrane permeability. In fact,
this is the real power of logP determinations, since we are referring to a
partitioning between lipid and water that relates well to what we are trying to
accomplish – achieve a therapeutic concentration of drug in plasma. While
logP is reflective of water solubility, it is a better indication of this critical
partitioning relationship. The following should clarify
The greater the polarity of the drug molecule, the greater the
solubility in the highly polar aqueous environment (like dissolves like).
Polarity is described by logP values, which expresses the
ratio of partitioning between octanol and water in exponential
terms
Since the logP partition ratio is defined as octanol over water
logP = (log)
the higher the number, the greater the lipid solubility, or
lipophilicity, or hydrophobicity. Conversely, the higher the
negative value, the greater the aqueous solubility, or
hydrophilicity, or lypophobicity
This is a log scale. MlogP = 0 indicates equal partitioning
between octanol and water. A MlogP = 2 between 2
structures indicates a 100x greater partitioning into octanol for
the second structure. Similarly, MlogP = -2 indicates a 100x
greater partitioning into water. Partitioning is reflective* of H2O
solubility. As an example, let’s consider an approximation
using ClogP values (ACD Solaris V4.67) between Celecoxib
and Rofecoxib
Celecoxib, ClogP = 3.01
H20 solubility = .007 mg/mL
1-octanol solubility = 7.87 mg/mL
7.87/.007 = 1124, MlogP = 3.05
Rofecoxib
ClogP = 1.63
H20 solubility = .009 mg/mL
1-octanol solubility = .117 mg/mL
.117/.009 = 13, Mlog13 = 1.11
1124/13 = 86.5, Mlog86.5 = 1.94 = 3.05 – 1.11
.007 mg/mL = .0007% (w/v%) solubility
.009 mg/mL = .0009% (w/v%) solubility
.009/.007 = 1.28, Mlog1.28 = .107
Clearly .107 does not correspond well to the
difference in logP values (notice that the slight
increase in water solubility for Rofecoxib is
accompanied by a tremendous loss in octanol
solubility)
Returning to solubility considerations, we must also consider how we wish to be
able to deliver a drug when considering optimal solubility characteristics
Let’s use chloramphenicol (logP = 1.02) as an example
Broad spectrum antibiotic with reasonable penetration into the CNS
(important as an alternative treatment for Meningitis)
Reserved for treatment of serious infections resistant to penicillin G
and ampicillin owing to serious toxicities (blood dyscrasias, bone
marrow depression)
LogP < .5 (3.3% H2O solubility) is generally taken to mean water
soluble
Chloramphenicol LogP > .5, but still enough solubility for bitter taste to
come through – enter palmitate ester as prodrug
However, Chloramphenicol is also used in settings where IV
administration is important. Here, we would like to increase the water
solubility such that there is no chance of precipitating out a lipophilic
species &/or decrease the amount of material that needs to be injected