Important parameters Physical-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 pKa’s at 25°C

Fractions of individual ionised forms can be rapidly calculated from either macro-or micro-pKa’s.

% 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

F+ F± F0 F-

Macro pKa pKa1=7.5 pka2=9.2

0.75 0.24 0.005 0

Micro pKa pKa1=7.5 pka2=8.8

pKa3=9.1

pka4=7.8

0.72 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 7.2

Blood 7.4

Colon 5-8

Duodenum (fasting) 4.4-6.6

Duodenum (fed) 5.2-6.2

Saliva 6.4

Small intestine 6.5

Stomach (fasting) 1.4-2.1

Stomach (fed) 3-7

Sweat 5.4

Urine 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/Lo

gP/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 CNS penetration around Log P = 2 ±0.7

For Oral absorption around Log P = 1.8 For Intestinal absorption Log P =1.35 For Colonic absorption Log P = 1.32 For Sub lingual absorption Log P = 5.5 For 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 (4-7)

logPBinding 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.

N

O

OOH

O

Cl

0.001% neutral

0.01%

0.1%

1%

10%

50% neutral

pKa=4.50

logP=4.25

For singly ionising acids in general:

log D = log P - log[1 + 10(pH-pKa)]

Relationship between logD, logP and pH for an acidic drug

-2

-1

0

1

2

3

4

5

2 3 4 5 6 7 8 9 10

pH

log

D

Indomethacin

Amlodipine

pKa=9.3

For singly ionising bases in general:

logD = logP - log[1 + 10(pKa-pH)]

pH - Distribution behaviour of bases

-3

-2

-1

0

1

2

3

4

-4

3 4 5 6 7 8 9 10 11

pH

log

D

NH

O

O

O

OCl

O

NH2

NH

O

O

O

OCl

O

NH3+

N

NH

SNH

N

NH

CN

CimetidinepKa=6.8

NH+

NH

SNH

N

NH

CN

-2.5

-2

-1.5

-1

-0.5

0

0.5

2 3 4 5 6 7 8 9 10 11 12

pH

log

D

pH - Distribution behaviour of amphoteric compounds OH

NH2

pKa1 = 4.4

OH

NH3+

O

NH2

pKa2 = 9.8

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 Ionization Center

4.8 Pyridine

10.9 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 1–8) lead us to conclude that this compound would be more susceptible to higher aqueous solubility and of lower lipophilicity in the body.