Pka, Log P, Log D and Absorption
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divyenshah3Pka, Log P, Log D and Absorption
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divyenshah3Physical-Chemical parameter:
Solubility Lipophilicity/Hydrophilicity Salt for and polymorps Chemical stability particle and powder properties pKa and ionization
Formulation principles Biological principles
Absorption Distribution Metabolism Elimination
For transportation of drug, it should be in solution and non-ionized. But non-ionized form have higher lipophilicity, and thus lower solubility. At physiological pH, the drug will be in both ionized and unionized form. The non-ionized spp. will get absorbed and thus it is regenerated for maintenance of equilibrium between ionized-non ionized spp.
Ionisation can be calculated using the Henderson Hasselbalch relationships: Acid: pH = pKa + log10[A-]/[HA] [A-]/[HA] =10(pH-pKa) Base:pH = pKa -log10[BH+]/[B] [BH+]/[B] =10(pKa-pH)
pKa values are temperature dependent in a non-linear and unpredictable way. Standard practice is to measure pKas at 25C Fractions of individual ionised forms can be rapidly calculated from either macro-or micro-pKas. % ionized = 100/[1+10x(pH-pKa)], where x=-1 for acid, and x=1 for base.
Acid
Base
The solubility of acidic compounds increases as the pH of the solution is increased (above the pKa) and the solubility of basic compounds increases as the pH is lowered below the pKa.
macro pKa
micro pKa
For molecules with one acidic and one basic group denote xa= 10[pH-pKa(Acid)] and xb= 10[pKa(Base)-pH] Neutral fraction F0= 1 / [xa+ xaxb+ xb+1] Zwitterion fraction F= xaxb/ [xa+ xaxb+ xb+1] Cation fraction F+= xb/ [xa+ xaxb+ xb+1] Anion fraction F-= xa/ [xa+ xaxb+ xb+1]
Fraction of Labetolol at pH 7.0 Calculated pKa Macro pKa Micro pKa pKa1=7.5 pka2=9.2 pKa1=7.5 pka2=8.8 pKa3=9.1 pka4=7.8 F+ 0.75 0.72 F F0 F-
0.24 0.005 0 0.27 0.01 0
About 85% of marketed drugs contain functional groups that are ionised to some extent at physiological pH (pH 1.5 8). The acidity or basicity of a compound plays a major role in controlling: Absorption and transport to site of action Solubility, bioavailability, absorption and cell penetration, plasma binding, volume of distribution Binding of a compound at its site of action un-ionised form involved in hydrogen bonding ionised form influences strength of salt bridges or H-bonds Elimination of compound Biliary and renal excretion CYP P450 metabolism
Fluid
pH
Aqueous humour
Blood Colon Duodenum (fasting) Duodenum (fed) Saliva Small intestine Stomach (fasting) Stomach (fed) Sweat Urine
7.2
7.4 5-8 4.4-6.6 5.2-6.2 6.4 6.5 1.4-2.1 3-7 5.4 5.5-7
So the same compound will be ionised to different extents in different parts of the body. This means that, for example, basic compounds will not be so well absorbed in the stomach than acidic compounds since it is generally the unionised form of the drug which diffuses into the blood stream.
http://www.manuelsweb.com/pka.htm http://www.raell.demon.co.uk/chem/calcs/L ogP/perion.htm
E.g., A basic drug with a pKa of 7.8 is a known teratogen. If given IV to a pregnant woman whose blood pH is 7.4, will this drug cross the placenta and effect the baby?
From pH 11 to 7 potency increases since active species is the anion. From pH 7 to 3 potency decreases since only the neutral form of the compound can transport into the cell.
Aminoglycosides (e.g., gentamicin) are the exception to the general rule in that the uncharged species is insufficiently lipid soluble to cross the membrane appreciably. This is due to a preponderance of hydrogen bonding groups in the sugar moiety that render the uncharged molecule hydrophilic.
It is a measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation. Octanol/water system is mostly used because
Po/w is fairly easy to measure Po/w often correlates well with many biological properties It can be predicted fairly accurately using computational models
For For For For For For
CNS penetration around Log P = 2 0.7 Oral absorption around Log P = 1.8 Intestinal absorption Log P =1.35 Colonic absorption Log P = 1.32 Sub lingual absorption Log P = 5.5 Percutaneous Log P = 2.6 (& low mw)
Injectable -Low Log P (below 0) Oral -Medium (0-3) Transdermal -High (3-4) Toxic build up in fatty tissues - Very High (47)
logP
Binding to enzyme / receptor
Aqueous solubility
Binding to P450 metabolising enzymes
Absorption through membrane
Binding to blood / tissue proteins less drug free to act
Binding to hERG heart ion channel cardiotoxicity risk
So log P needs to be optimised
Elimination
Transporter effects on drug disposition
It is the effective lipophilicity of a compound at a given pH, and is a function of both the lipophilicity of the un-ionised compound and the degree of ionisation.
Relationship between logD, logP and pH for O an acidiclogP=4.25 drug O
5 4 3
OH
50% neutral 10%
N O
1%
logD 2
0.1%
1
Cl
Indomethacin
0.01% 0.001% neutral
0 -1 -2 2 3 4 5 6 7 8 9 10
pH
For singly ionising acids in general:
pKa=4.50
log D = log P - log[1 + 10(pH-pKa)]
pH - Distribution behaviour of bases
4
O Cl O O O N H Cl O O N H O O
3 2 1 logD 0 -1 -2 -3 -4 3 4 5 6 7 pH 8 9 10 11
H N NH+ S N H CN N N H
Amlodipine pKa=9.3
NH2
NH3+
H N N S N H
CN N N H
Cimetidine pKa=6.8
For singly ionising bases in general: logD = logP - log[1 + 10(pKa-pH)]
pH - Distribution behaviour of amphoteric OH compounds
pKa1 = 4.4
0.5 0 -0.5 logD -1 -1.5
pKa2 = 9.8
NH2
OH
-2
NH3+
-2.5 2 3 4 5 6 7 pH 8 9 10 11 12
NH2
To address lipophilicity concerns many companies have deployed computational alerts based on Log P which can lead to incorrect conclusions for ionizable compounds. The log P should be calculated at pH where the drug is in neutral/un-ionized form.
pKa
4.8 10.9
Ionization Center
Pyridine Piperidine
The compound shows a preference to be associated with the lipid phase (>30 fold affinity for octanol over water). Will likely permeate biological membranes
It is obvious from this plot of log D versus pH, that ionization of the compound greatly affects octanol-water partitioning and that lipophilicity cannot be simplified to a constant.
Negative values of logD (-1.44 to 0) in the physiologically relevant pH range (pH 18) lead us to conclude that this compound would be more susceptible to higher aqueous solubility and of lower lipophilicity in the body.