Throughout this presentation, emphasis has been placed on the water-solubilizing properties of the common organic functional groups. This is restated in Table 18.1 with carbon-solubilizing potentials for each functional group, and the use of these values was demonstrated by the examples shown in Figures 18.4 and 18.5. While this approach is empiric, others have attempted to derive an analytic method for cal-culation of water solubility. One such mathematical approach is based upon the par-titioning of a drug between octanol (a standard for lipophilic media) and water. The base-ten logarithm of the partition coefficients is defined as log P. While the meas-ured log P values are a measure of the solubility characteristics of the whole mole-cule, one can use fragments of the whole molecule and assign a specific hydrophilic-lipophilic value (defined as π value) to each of these fragments. Thus, a calculated log P can be obtained by the sum of the hydrophilic-lipophilic fragments:
log P Conc. of Drug in Octanol (Eq. 1)
Conc. of Drug in Water
log Pcalc π(fragments) (Eq. 2)
To use this procedure, the student must fragment the molecule into basic units and assign an appropriate π value corresponding to the atoms or groups of atoms pres-ent. Table 18.2 lists the common fragments found in organic molecules and their
Table 18.2. HYDROPHILIC-LIPOPHILIC VALUES (π VALUES) FOR ORGANIC FRAGMENTS
FRAGMENTS VALUES
C (aliphatic) C (alkene) Phenyl Cl (halogen)
O2NO S
O C O
O C N (other than amine) O (hydroxyl, phenol, ether) N (amine)
O2N (aliphatic) O2N (aromatic)
IMHB
0.5
0.33
2.0
0.5
0.0
1.0
1.0
0.85
0.28
0.7
0.7
0.2
0.65
C H A P T E R 1 8 nP R E D I C T I N G W AT E R S O L U B I L I T Y 161
π values. Positive values for π mean that the fragment, relative to hydrogen, is lipophilic or favors solubility in octanol. A negative value indicates a hydrophilic group and thus an affinity for water. While the environment of the substituent can influence the π value, such changes are small, and for our purposes this factor can be neglected.
Through the examination of a large number of experimentally obtained log P and solubility values, an arbitrary standard has been adopted whereby those chem-icals with a positive log P value over 0.5 are considered water-insoluble (i.e., sol-ubility is less than 3.3% in water—a definition for solsol-ubility used by the USP). Log P values less than 0.5 are considered water-soluble.
This method of calculating water solubility has proved quite effective with a large number of organic molecules containing C, Cl, N, and O, but several addi-tional factors may have to be considered for specific drugs. A complicating factor is the influence of intramolecular hydrogen bonding (IMHB) on π values. As dis-cussed in the previous empiric approach to predicting water solubility, IMHB would be expected to decrease water solubility, and, therefore, where IMHB ex-ists, a π value of 0.65 is added to the calculations. An example of using this fac-tor is shown for salicylic acid (Fig. 18.6).
OCOH OH
OC O O
H
H
Intramolecular H-bonding
Solubility 0.2%
Calc. log P without IMHB Calc. log P with IMHB Phenyl... +2.0 Phenyl... +2.0
O-H... –1.0 O-H... –1.0 O=C-O... –0.7 O=C-O... –0.7 Total... +0.3 IMHB... +0.65
Total... +0.95 Prediction Soluble Prediction Insoluble
FIGURE 18-6. Calculation of water solubility of salicylic acid without and with the intramolecular hydrogen bonding (IMHB) factor.
The log P values of a drug with acid or base character are influenced by the pH of the media in which the drug is placed. This is not surprising, since acid or base groups will become ionic under appropriate conditions. Although the π values given in Table 18.2 were obtained under conditions in which the amine, phenol, or carboxylic acid are unionized, which would allow an accurate prediction of log P, observed log Ps at various pH values may not be accurate for water prediction. The experimental log Ps found for procaine are −0.32 (pH 7) and 0.14 (pH 8), both of
R E V I E W O F O R G A N I C F U N C T I O N A L G R O U P S 162
which would lead to the prediction that procaine is water-soluble. In fact, procaine is soluble to the extent of 0.5% at pH 7. The calculated log P 2.3 (Fig. 18.7) correctly predicts that procaine is water insoluble.
H2N C
O
O CH2 CH2 N C2H5 C2H5
Procaine
Phenyl... +2.0 6 - C @ +0.5... + 3.0 O=C-O ... –0.7 Total... +2.3 2 - N @ –1.0 ... –2.0
Prediction Insoluble
FIGURE 18-7. Calculation of water solubility of procaine.
C a s e S t u d y 1 8 . 1
You are working the “graveyard” shift in the county hospital pharmacy when a call comes in from the ER. LN, a 21-year-old anorexic woman seriously injured in a car accident, has just been brought in by ambulance. LN is 5′8″ and weighs 102 pounds. She is in significant pain, and the physician wants your opinion on which of three opioid analgesics drawn below would be best to use in this situa-tion. The opioid, in salt form, will be administered intravenously.
O OH HO
N H3C
Morphine
HO
N H3C
O HO
N H2C
Buprenorphine
OCH3 CH3 OHCH3
CHCH33
Levorphanol You inform this physician that opioids are relatively lipophilic structures, and they attempt to get out of the aqueous circulation by distributing into body fat
C H A P T E R 1 8 nP R E D I C T I N G W AT E R S O L U B I L I T Y 163
C a s e S t u d y 1 8 . 1
(continued)(a peripheral storage site) and brain (the site of action). Drug manufacturers take this into account when establishing the dose. In a person of normal body weight, the amount of drug reaching the brain is enough to induce analgesia, but not enough to cause life-threatening side effects like respiratory depression. The more lipophilic the drug, the more readily it is sequestered into the fat, and the more willingly it will cross the blood-brain barrier from the bloodstream.
After reminding LN’s attending of this important pharmacokinetic reality, you evaluate the impact of the functional groups of the three opioid structures on relative water/lipid solubility and make your decision. Which opioid will you rec-ommend for LN?
C a s e S t u d y 1 8 . 2
You are doing an early experiential rotation shadowing in a compounding phar-macy. You are learning that emulsions can be of two main types, that is, oil-in-water (O/W) and water-in oil (W/O). You also learned that O/W emulsions are carriers for lipophilic drugs and W/O emulsions are carriers for hydrophilic drugs.
Since the precepting pharmacist knows you like chemistry and have had the course in organic functional groups, he presents you with the following three drugs and asks you if you would emulsify them in O/W or W/O emulsions. By looking at their structures and using the water-solubilizing potential of organic functional groups found in Table 18.1, predict which media you will use for your emulsions.
O
O O
O CH2OH
HO HO HO HO
O OH CH2OH
HO HO CH3
HO HO HO
NH OH
1
N N
HN
COOH O
F
2
O
HO
C OH H3C
O OCH3
3