USING THE POLARITY CHARACTERISTICS OF A DRUG’S FUNCTIONAL GROUPS TO ESTIMATE SOLUBILITY CHARACTERISTICS

Lesson Objectives

1. Understand what is meant by logP; know the difference between MlogP and ClogP

2. Utilize the polarity of a drug molecules functional groups to estimate the water solubility and permeability capacity of that drug molecule

3. Know the general limits to logP for ability to cross lipid membranes (transition through various biological compartments such as gut and vasculature)

4. Know the general limits to logP for ability to show sufficient solubility in water

5. Know how the limits to membrane permeability can be used to therapeutic advantage, as in the case of Mannitol and Sorbitol

6. 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. 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

b. 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 Good oral availability o 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 Also third generation cephalosporin, with similar profile to ceftriaxone

o 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 Peak plasma in 3-7 hrs

o Steady state plasma levels not reached until 1-5 months of daily therapy

o Onset of action 2-3 months

o Huge volume of distribution 70 L/kg, Huge elimination half-life

with persistence of side effects

� Halofantrine (8.86)

o Synthetic antimalarial related to mefloquine and quinine o Absorption is poor and widely varied on an empty stomach but

is increased ca. 10x with a high fat meal

o 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