Download Solubility # 6

Solubility ( # 6)
King Saud University
College of Pharmacy
Pharm. Chem. Dept.
PHC 271
1428/1429 H
Lec.# 6
Receptors
⇒ The structurally specific drugs exhibit their biological activity via interaction with
specific cellular component called receptors
⇒ Receptor may refer to:
•
Sensory receptor, in physiology, any structure which, on receiving
environmental stimuli, produces an informative nerve impulse.
•
Receptor (immunology), a molecule on the surface of an immunocyte which
binds its ligand.
•
Receptor (biochemistry), is a protein on the cell membrane or within the
cytoplasm or cell nucleus that binds to a specific molecule (a ligand) such as a
neurotransmitter or a hormone or other substance, and initiates the cellular
response to the ligand.
⇒ The shapes and actions of receptors are newly investigated by the X-ray
crystallography and computer modeling. This increases the current
understanding of drug action at binding sites on the receptors.
Types of receptors:
Receptors exist in different types, dependent on their ligand and function:
1. Enzyme; e.g. Acetylcholine esterase enzyme (Insecticides).
2. Peripheral membrane proteins; e.g. the regulatory protein subunits of many
ion channels (Local anesthetics).
3. Intracellular proteins such as those for steroid hormone receptors, e.g.
estrogen receptor (Tamoxifen). These receptors often can enter the cell
nucleus and modulate gene expression in response to the activation by the
ligand.
4. Transmembrane proteins such as neurotransmitter receptors (α- and βadrenergic receptors).
Drug-Receptor Interaction:
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Solubility ( # 6)
Applications of Henderson-Hassalbalch Equation
The concept of pKa not only indicates the relative acid-base strength of organic
functional groups but also allows one to calculate, for a given pH, exactly how much of
the molecule is in the ionized and un-ionized form, which therefore allows prediction of
absorption, relative water solubility, and excretion for a given compound.
Examples:
1) The pH of the stomach is 2.5. The pKa of sodium pentothal is 7.4 and it is acidic
compound. If a patient is given sodium pentothal orally instead of IV, will it put the
patient to sleep?
•
None of the sodium pentothal is ionized
in the stomach. Therefore the patient
would absorb 100% of this medication
and it would put him to sleep.
Sodium Thiopental
2) 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?
In this example, 72% of the drug is ionized which means 28% of the drug is
unionized and will pass through the placenta to effect the baby.
100
⇒ Percent Ionization Formula:
1 + 10 x (pH – pKa)
Where x = -1 if acid drug or 1 if basic drug
⇒ Basic Rules:
ü If pKa – pH = 0, then 50% of drug is ionized and 50% is unionized
ü If pKa – pH = 0.5, then 75% of drug is ionized and 25% is unionized or
75% unionized and 25% ionized.
ü If pKa – pH > 1, then the drug is 99 – 100% ionized or 99 – 100%
unionized.
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Solubility ( # 6)
⇒ Amphoteric drug: that is, it act as an aid or a base, depending on the condition,
Example: Ciprofloxacin, a fluroquinolone antibiotic contains a secondary alkyl amine,
two tertiary arylamines, and a carboxylic acid.
30 arylamine
(weak base)
20 amine
(basic)
Carboxylic acid
(acidic)
Fig. 1: Chemical Structure of Ciprofloxacin Showing the Various Organic Functional
Groups.
O
O
N
H
COO
N
N
H
N
F
COOH
F
N
H
H
Stomach (pH 1 - 3.5)
Colon (pH 5.6 - 7)
Fig. 2: Predominant forms of Ciprofloxacin at two Different Locations within the
Gastrointestinal Tract.
II. Solubility:
The term solubility refer to solubilization of the drug in the different media, polar
solvent as water (hydrophilic character) and non-polar solvent as lipid (hydrophobic or
lipophilic character).
a) Water solubility:
⇒ The solubility of a drug molecule in water greatly affects the routes of
administration that are available as well as its absorption, distribution,
and elimination.
⇒ Two key concepts to keep in mind when considering the water (or lipid)
solubility of a molecule are:
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Solubility ( # 6)
•
•
The hydrogen bond-forming potential of the function groups
in the molecule.
The ionization of functional groups.
Hydrogen Bonds:
•
•
Each functional group capable of donating or accepting a hydrogen bond will
contribute to the overall water solubility of the compound and increase the
hydrophilic nature of the molecule.
Hydrogen bonds are referred to as dipole-dipole bonds.
H
H
H
O
H
H
H
O
H
O
O
H
N
H
H
O
O
H
H
R
R
Fig. 1: Examples of Hydrogen-Bonding Between water and Hypothetical Drug Molecules.
Ionization:
Another type of bonding interaction plays an important role in determining water
solubility, ion-dipole interaction.
O
H
H
O
H
O
H
H
N
H
O
h
Fig. 2: Examples of Ion-dipole Interactions.
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Solubility ( # 6)
b) lipid solubility and partition coefficient (P):
⇒ Some drugs, even they are in the un-ionized form, they are poorly absorbed
from GIT, thisis because of their low lipid solubility.
⇒ A guide for the lipid solubility or the lipophilic nature of a drug is known as
partition coefficient (p).
⇒ The partition coefficient, P, refers to the ratio of the concentrations of the
drug in octanol to that in water. Octanol is used to mimic amphiphilic
nature of lipid, because it has a primary alcohol) and a long hydrocarbon
chain, such as that of fatty acids, which make up part of a lipid membrane.
⇒ The concentration of the drug in both layers is determined by appropriate
analytical technique.
[drug] lipid
⇒ P=
[drug] octanol
=
[drug] water
[drug] water
For simplicity log P is used instead of P
[drug] octanol
Log P =
[drug] water
⇒ Hydrophobic (lipophilic) compounds will have a high log P and achieve
good absorption from GIT.
⇒ Hansch used partition coefficient to relate a physical properties to
biological effect by studying the P for a series of CNS hypnotics.
Drug
Chem. Structure
Log P
Barbituric acid
derivatives
CH3
Glutathimide
CH3
O
N
O
H
Chlorbutanol
OH
H3 C
C
CCl3
CH3
Chloroform
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